JP7590343B2 - Modulators of the integrated stress response pathway - Google Patents

Description

の化合物、または薬学的に許容される塩、溶媒和物、水和物、互変異性体もしくは立体異性体（式中、Ｒ^１、Ｒ^２、Ｒ^２ａ、Ｒ^３、Ｒ^ａ２、Ｒ^ａ４、Ｒ^ａ５、Ｒ^ａ６、Ｒ^ａ７、Ｘ^１、Ｘ^１ａ、Ａ^１およびＡ^２は、本記載および請求項に示されている通りの意味を有する）に関する。本発明は、前記化合物を含む医薬組成物、医薬としてのそれらの使用ならびに統合ストレス応答と関連する１つまたはそれ以上の疾患または障害を処置および防止するための方法におけるそれらの使用にさらに関する。 The present invention relates to a compound represented by formula (I)

or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein ^R1 , R2, ^R2a , ^R3 , R ^a2 , R ^{a4 ,} R ^a5 , R ^a6 , R ^a7 , ^X1 , ^X1a , ^A1 and ^A2 have the meanings as set out in the description and claims. The invention further relates to pharmaceutical compositions comprising said compounds, their use as medicaments and their use in methods for treating and preventing one or more diseases or disorders associated with the integrated stress response.

The integrated stress response (ISR) is a cellular stress response common to all eukaryotes (1). Dysregulation of ISR signaling has important pathological consequences leading to inflammation, viral infections, diabetes, cancer and neurodegenerative diseases, among others.

ISR is a common factor in different types of cellular stress that results in phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) on serine 51, leading to the suppression of normal protein synthesis and expression of stress-responsive genes (2). In mammalian cells, the phosphorylation is carried out by a family of four eIF2alpha kinases, each of which responds to distinct environmental and physiological stresses: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), heme-regulated eIF2alpha kinase (HRI), and general control non-derepressible 2 (GCN2) (3).

eIF2alpha, together with eIF2beta and eIF2gamma, forms the eIF2 complex, a key player in normal initiation of mRNA translation (4). The eIF2 complex binds GTP and Met- _tRNAi to form the ternary complex (eIF2-GTP-Met-tRNAi ₎ that is recruited by the ribosome for translation initiation (5, 6).

eIF2B is a heterodecamer complex consisting of five subunits (alpha, beta, gamma, delta, and epsilon) that in duplicate form a GEF-active decamer (7).

In response to ISR activation, phosphorylated eIF2alpha inhibits eIF2B-mediated exchange of GDP with GTP, resulting in reduced ternary complex formation and therefore inhibition of translation of normal mRNAs characterized by ribosome binding to the 5'AUG start codon (8). Under these conditions of reduced ternary complex abundance, translation of several specific mRNAs, including the mRNA encoding the transcription factor ATF4, is activated through a mechanism that involves altered translation of upstream ORFs (uORFs) (7, 9, 10). These mRNAs typically contain one or more uORFs that function normally in unstressed cells to restrict ribosome flow to the main coding ORF. For example, in normal conditions, uORFs in the 5'UTR of ATF occupy ribosomes and prevent translation of the coding sequence of ATF4. However, during stress conditions, i.e., under conditions of reduced ternary complex formation, the probability that ribosomes will scan past these upstream ORFs and begin translation at the ATF4-encoding ORF is increased. ATF4 and other stress response factors expressed in this manner subsequently direct the expression of an array of further stress response genes. The acute phase consists in the expression of proteins aimed at restoring homeostasis, while the chronic phase leads to the expression of pro-apoptotic factors (1, 11, 12, 13).

Upregulation of markers of ISR signaling has been demonstrated in a variety of conditions, among these cancers and neurodegenerative diseases. In cancer, ER stress-regulated translation increases resistance to hypoxic conditions and promotes tumor growth (14, 15, 16), and genetically targeted deletion of PERK has been shown to retard the growth of tumors derived from transformed PERK ^−/− mouse embryonic fibroblasts (14, 17). Furthermore, a recent report provided proof of concept that activators of eIF2B are effective in treating an aggressive form of metastatic prostate cancer using patient-derived xenograft modeling in mice (28). Taken together, prevention of cytoprotective ISR signaling may represent an effective antiproliferative strategy for the treatment of at least some forms of cancer.

Furthermore, modulation of ISR signaling could prove effective in preserving synaptic function and reducing neuronal attenuation, as well as in neurodegenerative diseases characterized by activation of the misfolded and unfolded protein response (UPR), such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD) and Jakob Creutzfeldt (prion) disease (18, 19, 20). There are examples of neurodegenerative diseases in which it has been shown that pharmacological as well as genetic inhibition of ISR signaling can normalize protein translation levels, rescue synaptic function and prevent neuronal loss, as for prion diseases (21). Specifically, reduction of the levels of phosphorylated eIF2alpha by overexpression of a phosphatase that controls phosphorylated eIF2alpha levels increased survival time of prion-infected mice, whereas maintained eIF2alpha phosphorylation reduced survival time (22).

Furthermore, direct evidence for the importance of controlling protein expression levels for proper brain function exists in the form of rare genetic diseases that affect the function of eIF2 and eIF2B. Mutations in eIF2 gamma that disrupt the eIF2 complex integrity and therefore result in a reduction in normal protein expression levels lead to intellectual disability syndrome (ID) (23). Partial loss of function mutations in subunits of eIF2B have been shown to be the cause of rare leukodystrophic vanishing white matter disease (VWMD) (24, 25). Specifically, stabilization of eIF2B partial loss of function in VWMD mouse models with small molecules related to ISRIB has been shown to reduce ISR markers and improve functional as well as pathological endpoints (26, 27).

Modulators of the eIF2alpha pathway are described in U.S. Patent No. 5,393,666; U.S. Patent No. 5,433,363; U.S. Patent No. 5,433,363; and U.S. Patent No. 5,523,633 describe modulators of the integrated stress pathway. U.S. Patent No. 5,433,666; U.S. Patent No. 5,433,633; U.S. Patent No. 5,433,633; and U.S. Patent No. 5,433,633 describe inhibitors of the ATF4 pathway. U.S. Patent No. 5,433,666 and U.S. Patent No. 5,433,633 relate to eukaryotic initiation factor 2B modulators.

Further documents describing modulators of the integrated stress pathway are US Pat. No. 5,399,663, US Pat. No. 5,493,326, US Pat. No. 5,523,636, US Pat. No. 5,523,666, US Pat. No. 5,523,671 ...

However, there is a continuing need for new compounds useful as modulators of the integrated stress response pathway that have favorable pharmacokinetic properties.

WO2014/144952A2 WO2017/193030A1 WO2017/193034A1 WO2017/193041A1 WO2017/193063A1 WO2017/212423A1 WO2017/212425A1 WO2018/225093A1 WO2019/008506A1 WO2019/008507A1 WO2019/032743A1 WO2019/046779A1 WO2019/090069A1 WO2019/090074A1 WO2019/090076A1 WO2019/090078A1 WO2019/090081A1 WO2019/090082A1 WO2019/090085A1 WO2019/090088A1 WO2019/090090A1 WO2019/183589A1 WO2019/118785A2 WO2019/193540A1 WO2019/193541A1

The object of the present invention is therefore to provide a new class of compounds as modulators of the integrated stress response pathway that may be effective in the treatment of integrated stress response pathway-associated diseases and that may have improved pharmacologic relevant properties, including activity, solubility, selectivity, ADMET properties and/or reduced side effects.

の化合物、またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体もしくは立体異性体（式中、
Ｘ^１は、Ｎ（Ｒ^ａ１）であり；
Ｘ^１ａは、共有結合的単結合、ＣＨ（Ｒ^ａ３）またはＣＨ（Ｒ^ａ３）ＣＨ_２であり；
Ｒ^ａ１は、Ｈ、Ｃ（Ｏ）ＯＣ_１－４アルキルまたはＣ_１～４アルキルであり、ここで、Ｃ（Ｏ）ＯＣ_１－４アルキルおよびＣ_１～４アルキルは、ハロゲン、ＯＨおよびＯ－Ｃ_１～３アルキルからなる群から選択される１個またはそれ以上の置換基で場合により置換されており、ここで、置換基は同じまたは異なり；
Ｒ^ａ２、Ｒ^ａ３は、Ｈ；ＯＨ；ＯＣ_１－４アルキル；ハロゲン；Ｃ_１～４アルキル；およびＡ^２ａからなる群から独立して選択され；
Ｒ^ａ４、Ｒ^ａ５、Ｒ^ａ６、Ｒ^ａ７は、Ｈ；ハロゲン；Ｃ_１～４アルキル；およびＡ^２ａからなる群から独立して選択され、
ただし、Ｒ^ａ２、Ｒ^ａ３、Ｒ^ａ４、Ｒ^ａ５、Ｒ^ａ６、Ｒ^ａ７の１つだけがＡ^２ａであるか；
またはＲ^ａ１ならびにＲ^ａ２およびＲ^ａ３の１つは、メチレンもしくはエチレン基を形成するか；
またはＲ^ａ１およびＲ^ａ６は、エチレン基を形成するか；
またはＲ^ａ２およびＲ^ａ５は、共有結合的単結合を形成するか；
またはＲ^ａ５、Ｒ^ａ７は、接続されることで、オキソ基を形成し；
Ａ^１は、Ｃ_５シクロアルキレン、Ｃ_５シクロアルケニレン、または窒素環原子含有５員ヘテロシクレン、ここで、Ａ^１は、同じまたは異なる１つまたはそれ以上のＲ^４で場合により置換されており；
各Ｒ^４は独立して、環が少なくとも部分的に飽和されているオキソ（＝Ｏ）、環が少なくとも部分的に飽和されているチオオキソ（＝Ｓ）、ハロゲン、ＣＮ、ＯＲ^５、またはＣ_１～６アルキルであり、ここで、Ｃ_１～６アルキルは、同じまたは異なる１つまたはそれ以上のハロゲンで場合により置換されており；
Ｒ^５は、ＨまたはＣ_１～６アルキルであり、ここで、Ｃ_１～６アルキルは、同じまたは異なる１つまたはそれ以上のハロゲンで場合により置換されており；
Ａ^２は、Ｒ^６ａまたはＡ^２ａであり；
Ｒ^６ａは、ＯＲ^６ａ１、ＳＲ^６ａ１、Ｎ（Ｒ^６ａ１Ｒ^６ａ２）；Ｃ_１～６アルキル、Ｃ_２～６アルケニルまたはＣ_２～６アルキニルであり、ここで、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルは、ハロゲン；ＣＮ；ＯＲ^６ａ３；およびＡ^２ａからなる群から選択される１個またはそれ以上の置換基で場合により置換されており、ここで、置換基は同じまたは異なり；
Ｒ^６ａ１、Ｒ^６ａ２は、Ｈ；Ｃ_１～６アルキル；Ｃ_２～６アルケニル；Ｃ_２～６アルキニル；およびＡ^２ａからなる群から独立して選択され、ここで、Ｃ_１～６アルキル；Ｃ_２～６アルケニル；およびＣ_２～６アルキニルは、ハロゲン；ＣＮ；ＯＲ^６ａ３；ＯＡ^２ａおよびＡ^２ａからなる群から選択される１個またはそれ以上の置換基で場合により置換されており、ここで、置換基は同じまたは異なり；
Ｒ^６ａ３は、Ｈ；またはＣ_１～４アルキルであり、ここで、Ｃ_１～４アルキルは、同じまたは異なる１つまたはそれ以上のハロゲンで場合により置換されており；
Ａ^２ａは、フェニル；Ｃ_３～７シクロアルキル；Ｃ_４～１２ビシクロアルキル；または３員から７員のヘテロシクリルであり、ここで、Ａ^２ａは、同じまたは異なる１つまたはそれ以上のＲ^６で場合により置換されており；
各Ｒ^６は独立して、Ｒ^６ｂ；ＯＨ；ＯＲ^６ｂ；ハロゲン；もしくはＣＮであり、ここで、Ｒ^６ｂは、シクロプロピル、Ｃ_１～６アルキル；Ｃ_２～６アルケニル；もしくはＣ_２～６アルキニルであり、ここで、Ｒ^６ｂは、同じもしくは異なる１つもしくはそれ以上のハロゲンで場合により置換されているか；または
２つのＲ^６は、接続されることで、それらが付着されている原子と一緒に、環Ａ^２ｂを形成し；
Ａ^２ｂは、フェニル；Ｃ_３～７シクロアルキル；または３員から７員のヘテロシクリルであり、ここで、Ａ^２ｂは、同じまたは異なる１つまたはそれ以上のＲ^７で場合により置換されており；
各Ｒ^７は独立して、Ｃ_１～６アルキル、Ｃ_２～６アルケニルまたはＣ_２～６アルキニルであり、ここで、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルは、同じまたは異なる１つまたはそれ以上のハロゲンで場合により置換されており；
Ｒ^１は、ＨまたはＣ_１～４アルキル、好ましくはＨであり、ここで、Ｃ_１～４アルキルは、同じまたは異なる１つまたはそれ以上のハロゲンで場合により置換されており；
Ｒ^２は、Ｈ；Ｆ；もしくはＣ_１～４アルキルであり、ここで、Ｃ_１～４アルキルは、同じもしくは異なる１つもしくはそれ以上のハロゲンで場合により置換されており；
Ｒ^３は、Ａ^３、Ｃ_１～６アルキル、Ｃ_２～６アルケニルもしくはＣ_２～６アルキニルであり、ここで、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルは、同じもしくは異なる１つもしくはそれ以上のＲ^８で場合により置換されているか；または
Ｒ^２およびＲ^３は、接続されることで、酸素原子およびそれらが付着されている炭素原子と一緒に、環Ａ^３ａを形成し、ここで、Ａ^３ａは、７員から１２員のヘテロビシクリルであり、ここで、７員から１２員のヘテロビシクリルは、同じもしくは異なる１つもしくはそれ以上のＲ^１０で場合により置換されており；
Ｒ^２ａは、ＨまたはＦ、好ましくはＨであり；
各Ｒ^８は独立して、ハロゲン；ＣＮ、Ｃ（Ｏ）ＯＲ^９、ＯＲ^９、Ｃ（Ｏ）Ｒ^９、Ｃ（Ｏ）Ｎ（Ｒ^９Ｒ^９ａ）、Ｓ（Ｏ）_２Ｎ（Ｒ^９Ｒ^９ａ）、Ｓ（Ｏ）Ｎ（Ｒ^９Ｒ^９ａ）、Ｓ（Ｏ）_２Ｒ^９、Ｓ（Ｏ）Ｒ^９、Ｎ（Ｒ^９）Ｓ（Ｏ）_２Ｎ（Ｒ^９ａＲ^９ｂ）、ＳＲ^９、Ｎ（Ｒ^９Ｒ^９ａ）、ＮＯ_２、ＯＣ（Ｏ）Ｒ^９、Ｎ（Ｒ^９）Ｃ（Ｏ）Ｒ^９ａ、Ｎ（Ｒ^９）ＳＯ_２Ｒ^９ａ、Ｎ（Ｒ^９）Ｓ（Ｏ）Ｒ^９ａ、Ｎ（Ｒ^９）Ｃ（Ｏ）Ｎ（Ｒ^９ａＲ^９ｂ）、Ｎ（Ｒ^９）Ｃ（Ｏ）ＯＲ^９ａ、ＯＣ（Ｏ）Ｎ（Ｒ^９Ｒ^９ａ）、またはＡ^３であり；
Ｒ^９、Ｒ^９ａ、Ｒ^９ｂは、Ｈ、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルからなる群から独立して選択され、ここで、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルは、同じもしくは異なる１つもしくはそれ以上のハロゲン、または１つのＯＨ、または１つのＯＣ_１－４アルキル、または１つのＡ^３で場合により置換されており；
各Ａ^３は独立して、フェニル、ナフチル、Ｃ_３～７シクロアルキル、３員から７員のヘテロシクリル、または７員から１２員のヘテロビシクリルであり、ここで、Ａ^３は、同じまたは異なる１つまたはそれ以上のＲ^１０で場合により置換されており；
各Ｒ^１０は独立して、ハロゲン、ＣＮ、Ｃ（Ｏ）ＯＲ^１１、ＯＲ^１１、Ｃ（Ｏ）Ｒ^１１、Ｃ（Ｏ）Ｎ（Ｒ^１１Ｒ^１１ａ）、Ｓ（Ｏ）_２Ｎ（Ｒ^１１Ｒ^１１ａ）、Ｓ（Ｏ）Ｎ（Ｒ^１１Ｒ^１１ａ）、Ｓ（Ｏ）_２Ｒ^１１、Ｓ（Ｏ）Ｒ^１１、Ｎ（Ｒ^１１）Ｓ（Ｏ）_２Ｎ（Ｒ^１１ａＲ^１１ｂ）、ＳＲ^１１、Ｎ（Ｒ^１１Ｒ^１１ａ）、ＮＯ_２、ＯＣ（Ｏ）Ｒ^１１、Ｎ（Ｒ^１１）Ｃ（Ｏ）Ｒ^１１ａ、Ｎ（Ｒ^１１）Ｓ（Ｏ）_２Ｒ^１１ａ、Ｎ（Ｒ^１１）Ｓ（Ｏ）Ｒ^１１ａ、Ｎ（Ｒ^１１）Ｃ（Ｏ）ＯＲ^１１ａ、Ｎ（Ｒ^１１）Ｃ（Ｏ）Ｎ（Ｒ^１１ａＲ^１１ｂ）、ＯＣ（Ｏ）Ｎ（Ｒ^１１Ｒ^１１ａ）、環が少なくとも部分に飽和されているオキソ（＝Ｏ）、Ｃ_１～６アルキル、Ｃ_２～６アルケニルまたはＣ_２～６アルキニルであり、ここで、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルは、同じまたは異なる１つまたはそれ以上のＲ^１２で場合により置換されており；
Ｒ^１１、Ｒ^１１ａ、Ｒ^１１ｂは、Ｈ、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルからなる群から独立して選択され、ここで、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルは、同じまたは異なる１つまたはそれ以上のハロゲンで場合により置換されており；
各Ｒ^１２は独立して、ハロゲン、ＣＮ、Ｃ（Ｏ）ＯＲ^１３、ＯＲ^１３、Ｃ（Ｏ）Ｒ^１３、Ｃ（Ｏ）Ｎ（Ｒ^１３Ｒ^１３ａ）、Ｓ（Ｏ）_２Ｎ（Ｒ^１３Ｒ^１３ａ）、Ｓ（Ｏ）Ｎ（Ｒ^１３Ｒ^１３ａ）、Ｓ（Ｏ）_２Ｒ^１３、Ｓ（Ｏ）Ｒ^１３、Ｎ（Ｒ^１３）Ｓ（Ｏ）_２Ｎ（Ｒ^１３ａＲ^１３ｂ）、ＳＲ^１３、Ｎ（Ｒ^１３Ｒ^１３ａ）、ＮＯ_２、ＯＣ（Ｏ）Ｒ^１３、Ｎ（Ｒ^１３）Ｃ（Ｏ）Ｒ^１３ａ、Ｎ（Ｒ^１３）ＳＯ_２Ｒ^１３ａ、Ｎ（Ｒ^１３）Ｓ（Ｏ）Ｒ^１３ａ、Ｎ（Ｒ^１３）Ｃ（Ｏ）Ｎ（Ｒ^１３ａＲ^１３ｂ）、Ｎ（Ｒ^１３）Ｃ（Ｏ）ＯＲ^１３ａ、またはＯＣ（Ｏ）Ｎ（Ｒ^１３Ｒ^１３ａ）であり；
Ｒ^１３、Ｒ^１３ａ、Ｒ^１３ｂは、Ｈ、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルからなる群から独立して選択され、ここで、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルは、同じまたは異なる１つまたはそれ以上のハロゲンで場合により置換されている）を提供する。 The present invention therefore relates to a compound of formula (I) for use as a medicament.

or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof,
^X1 is N(R ^a1 );
X ^1a is a covalent single bond, CH(R ^a3 ) or CH(R ^a3 )CH ₂ ;
R ^a1 is H, C(O)OC _1-4 alkyl or C _1-4 alkyl, where C(O)OC _1-4 alkyl and C _1-4 alkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, OH and O—C _1-3 alkyl, where the substituents are the same or different;
R ^a2 , R ^a3 are independently selected from the group consisting of H; OH; OC _1-4 alkyl; halogen; C _1-4 alkyl; and A ^2a ;
R ^a4 , R ^a5 , R ^a6 , R ^a7 are independently selected from the group consisting of H; halogen; C _1-4 alkyl; and A ^2a ;
with the proviso that only one of R ^a2 , R ^a3 , R ^a4 , R ^a5 , R ^a6 , and R ^a7 is A ^2a ;
or R ^a1 and one of R ^a2 and R ^a3 form a methylene or ethylene group;
or R ^a1 and R ^a6 form an ethylene group;
or R ^a2 and R ^a5 form a covalent single bond;
or R ^a5 and R ^a7 are connected to form an oxo group;
A ¹ is a C ₅ cycloalkylene, a C ₅ cycloalkenylene, or a nitrogen ring atom-containing 5-membered heterocyclene, where A ¹ is optionally substituted with one or more R ⁴ , which may be the same or different;
each R ⁴ is independently an at least partially saturated ring oxo (═O), an at least partially saturated ring thioxo (═S), halogen, CN, OR ⁵ , or C _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted with one or more halogens which may be the same or different;
R ⁵ is H or C _1-6 alkyl, where C _1-6 alkyl is optionally substituted with one or more halogens which may be the same or different;
^A2 is ^R6a or ^A2a ;
R ^6a is OR ^6a1 , SR ^6a1 , N(R ^6a1 R ^6a2 ); C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, where C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen; CN; OR ^6a3 ; and A ^2a , where the substituents are the same or different;
R ^6a1 , R ^6a2 are independently selected from the group consisting of H; C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; and A ^2a , where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen; CN; OR ^6a3 ; OA ^2a and A ^2a , where the substituents are the same or different;
R ^6a3 is H; or C _1-4 alkyl, wherein C _1-4 alkyl is optionally substituted with one or more halogens, which may be the same or different;
A ^2a is phenyl; C _3-7 cycloalkyl; C _{4-12 bicycloalkyl; or 3- to} 7-membered heterocyclyl, where A ^2a is optionally substituted with one or more R ⁶ , which may be the same or different;
each R ⁶ is independently R ^6b ; OH; OR ^6b ; halogen; or CN, where R ^6b is cyclopropyl, C _1-6 alkyl; C _2-6 alkenyl; or C _2-6 alkynyl, where R ^6b is optionally substituted with one or more halogens, which may be the same or different; or two R ⁶ are connected to form, together with the atom to which they are attached, a ring A ^2b ;
A ^2b is phenyl; C _3-7 cycloalkyl; or 3- to 7-membered heterocyclyl, where A ^2b is optionally substituted with one or more R ⁷ , which may be the same or different;
each R ⁷ is independently a C _1-6 alkyl, a C _2-6 alkenyl, or a C _2-6 alkynyl, wherein the C _1-6 alkyl, the C _2-6 alkenyl, and the C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different;
R ¹ is H or C _1-4 alkyl, preferably H, where C _1-4 alkyl is optionally substituted with one or more halogens which may be the same or different;
^R2 is H; F; or _C1-4 alkyl, where _C1-4 alkyl is optionally substituted with one or more halogens, which may be the same or different;
R ³ is A ³ , C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, where C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with one or more R ⁸ , which are the same or different; or R ² and R ³ are connected to form, together with the oxygen atom and the carbon atom to which they are attached, a ring A ^3a , where A ^3a is a 7- to 12-membered heterobicyclyl, where the 7- to 12-membered heterobicyclyl is optionally substituted with one or more R ¹⁰ , which are the same or different;
R ^2a is H or F, preferably H;
Each R ⁸ is independently halogen; CN, C(O)OR ⁹ , OR ⁹ , C(O)R ⁹ , C(O)N(R ⁹ R ^9a ), S(O) ₂ N(R ⁹ R ^9a ), S(O)N(R ⁹ R ^9a ), S(O) ₂ R ⁹ , S(O)R ⁹ , N(R ⁹ )S(O) ₂ N(R ^9a R ^9b ), SR ⁹ , N(R ⁹ R ^9a ), NO ₂ , OC(O)R ⁹ , N(R ⁹ )C(O)R ^9a , N(R ⁹ )SO ₂ R ^9a , N(R ⁹ )S(O)R ^9a , N(R ⁹ )C(O)N(R ^9a R ^9b ), N(R ⁹ )C(O)OR ^9a , OC(O)N(R ⁹ R ^9a ), or A ³ ;
R ⁹ , R ^9a , R ^9b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different, or one OH, or one OC _1-4 alkyl, or one A ³ ;
each A ³ is independently phenyl, naphthyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or 7- to 12-membered heterobicyclyl, where A ³ is optionally substituted with one or more R ¹⁰ , which are the same or different;
Each R ¹⁰ is independently halogen, CN, C(O)OR ¹¹ , OR ¹¹ , C(O)R ¹¹ , C(O)N(R ¹¹ R ^11a ), S(O) ₂ N(R ¹¹ R ^11a ), S(O)N(R ¹¹ R ^11a ), S(O) ₂ R ¹¹ , S(O)R ¹¹ , N(R ¹¹ )S(O) ₂ N(R ^11a R ^11b ), SR ¹¹ , N(R ¹¹ R ^11a ), NO ₂ , OC(O)R ¹¹ , N(R ¹¹ )C(O)R ^11a , N(R ¹¹ )S(O) ₂ R ^11a , N(R ¹¹ )S(O)R ^lla , N(R ¹¹ )C(O)OR ^11a , N(R ¹¹ )C(O)N(R ^11a R ^11b ), OC(O)N(R ¹¹ R ^11a ), oxo (═O) where the ring is at least partially saturated, C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with one or more R ¹² which may be the same or different;
R ¹¹ , R ^11a , R ^11b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different;
each R ¹² is independently halogen, CN, C(O)OR ¹³ , OR ¹³ , C(O)R ¹³ , C(O)N(R ¹³ R ^13a ), S(O) ₂ N(R ¹³ R ^13a ), S(O)N(R ¹³ R ^13a ), S(O) ₂ R ¹³ , S(O)R ¹³ , N(R ¹³ )S(O) ₂ N(R ^13a R ^13b ), SR ¹³ , N(R ¹³ R ^13a ), NO ₂ , OC(O)R ¹³ , N(R ¹³ )C(O)R ^13a , N(R ¹³ )SO ₂ R ^13a , N(R ¹³ )S(O)R ^13a , N( ^R13 )C(O)N ^{(R13aR13b )} , ^N ( ^R13 )C(O) ^OR13a , or OC(O)N( ^R13R13a );
R ¹³ , R ^13a , R ^13b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, and C _{2-6 alkynyl, wherein C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl are optionally} substituted with one or more halogens, which may be the same or different.

Compounds not limited to pharmaceutical use as defined above with the priority as defined below, and pharma- ceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof, are also within the scope of the present invention, with the exception of the following compounds or pharma-ceutically acceptable salts, solvates, hydrates, tautomers or stereoisomers thereof:

The excluded compounds represent commercially available compounds that do not have an indication of use.

The present invention also relates to a preferred compound of formula (I) or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein:
^X1 is N(R ^a1 );
X ^1a is a covalent single bond, CH(R ^a3 ), or CH(R ^a3 )CH ₂ ;
R ^a1 is H, C(O)OC _1-4 alkyl or C _1-4 alkyl, where C(O)OC _1-4 alkyl and C _1-4 alkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, OH, and O-C _1-3 alkyl, where the substituents are the same or different;
R ^a2 , R ^a3 are independently selected from the group consisting of H; OH; OC _1-4 alkyl; halogen; C _1-4 alkyl; and A ^2a ;
R ^a4 , R ^a5 , R ^a6 , R ^a7 are independently selected from the group consisting of H; halogen; C _1-4 alkyl; and A ^2a ;
with the proviso that exactly one of R ^a2 , R ^a3 , R ^a4 , R ^a5 , R ^a6 , and R ^a7 is A ^2a ;
or R ^a1 and one of R ^a2 and R ^a3 form a methylene or ethylene group;
or R ^a1 and R ^a6 form an ethylene group;
or R ^a2 and R ^a5 form a covalent single bond;
or R ^a5 and R ^a7 are connected to form an oxo group;
A ¹ is a C ₅ cycloalkylene, a C ₅ cycloalkenylene, or a nitrogen ring atom-containing 5-membered heterocyclene, where A ¹ is optionally substituted with one or more R ⁴ , which may be the same or different;
each R ⁴ is independently an at least partially saturated ring oxo (═O), an at least partially saturated ring thioxo (═S), halogen, CN, OR ⁵ , or C _1-6 alkyl, wherein C _1-6 alkyl is optionally substituted with one or more halogens which may be the same or different;
R ⁵ is H or C _1-6 alkyl, where C _1-6 alkyl is optionally substituted with one or more halogens which may be the same or different;
^A2 is ^R6a or ^A2a ;
R ^6a is OR ^6a1 , SR ^6a1 , N(R ^6a1 R ^6a2 ); C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, where C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen; CN; OR ^6a3 ; and A ^2a , where the substituents are the same or different;
R ^6a1 , R ^6a2 are independently selected from the group consisting of H; C _1-6 alkyl; C _2-6 alkenyl; C _2-6 alkynyl; and A ^2a , where C _1-6 alkyl; C _2-6 alkenyl; and C _2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen; CN; OR ^6a3 ; and A ^2a , where the substituents are the same or different;
R ^6a3 is H; or C _1-4 alkyl, where C _1-4 alkyl is optionally substituted with one or more halogens which may be the same or different;
A ^2a is phenyl; C _3-7 cycloalkyl; C _{4-12 bicycloalkyl; or 3- to} 7-membered heterocyclyl, where A ^2a is optionally substituted with one or more R ⁶ , which may be the same or different;
each R ⁶ is independently R ^6b ; OH; OR ^6b ; halogen; or CN, where R ^6b is cyclopropyl, C _1-6 alkyl; C _2-6 alkenyl; or C _2-6 alkynyl, where R ^6b is optionally substituted with one or more halogens, which may be the same or different; or two R ⁶ are connected to form, together with the atom to which they are attached, a ring A ^2b ;
A ^2b is phenyl; C _3-7 cycloalkyl; or 3- to 7-membered heterocyclyl, where A ^2b is optionally substituted with one or more R ⁷ , which may be the same or different;
each R ⁷ is independently a C _1-6 alkyl, a C _2-6 alkenyl, or a C _2-6 alkynyl, wherein the C _1-6 alkyl, the C _2-6 alkenyl, and the C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different;
R ¹ is H or C _1-4 alkyl, preferably H, where C _1-4 alkyl is optionally substituted with one or more halogens which may be the same or different;
^R2 is H; F; or _C1-4 alkyl, where _C1-4 alkyl is optionally substituted with one or more halogens, which may be the same or different;
R ³ is A ³ , C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, where C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with one or more R ⁸ , which are the same or different; or R ² and R ³ are connected to form, together with the oxygen atom and the carbon atom to which they are attached, a ring A ^3a , where A ^3a is a 7- to 12-membered heterobicyclyl, where the 7- to 12-membered heterobicyclyl is optionally substituted with one or more R ¹⁰ , which are the same or different;
R ^2a is H or F, preferably H;
Each R ⁸ is independently halogen; CN, C(O)OR ⁹ , OR ⁹ , C(O)R ⁹ , C(O)N(R ⁹ R ^9a ), S(O) ₂ N(R ⁹ R ^9a ), S(O)N(R ⁹ R ^9a ), S(O) ₂ R ⁹ , S(O)R ⁹ , N(R ⁹ )S(O) ₂ N(R ^9a R ^9b ), SR ⁹ , N(R ⁹ R ^9a ), NO ₂ , OC(O)R ⁹ , N(R ⁹ )C(O)R ^9a , N(R ⁹ )SO ₂ R ^9a , N(R ⁹ )S(O)R ^9a , N(R ⁹ )C(O)N(R ^9a R ^9b ), N(R ⁹ )C(O)OR ^9a , OC(O)N(R ⁹ R ^9a ), or A ³ ;
R ⁹ , R ^9a , R ^9b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different, or one OH, or one OC _1-4 alkyl, or one A ³ ;
each A ³ is independently phenyl, naphthyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or 7- to 12-membered heterobicyclyl, where A ³ is optionally substituted with one or more R ¹⁰ , which are the same or different;
Each R ¹⁰ is independently halogen, CN, C(O)OR ¹¹ , OR ¹¹ , C(O)R ¹¹ , C(O)N(R ¹¹ R ^11a ), S(O) ₂ N(R ¹¹ R ^11a ), S(O)N(R ¹¹ R ^11a ), S(O) ₂ R ¹¹ , S(O)R ¹¹ , N(R ¹¹ )S(O) ₂ N(R ^11a R ^11b ), SR ¹¹ , N(R ¹¹ R ^11a ), NO ₂ , OC(O)R ¹¹ , N(R ¹¹ )C(O)R ^11a , N(R ¹¹ )S(O) ₂ R ^11a , N(R ¹¹ )S(O)R ^lla , N(R ¹¹ )C(O)OR ^11a , N(R ¹¹ )C(O)N(R ^11a R ^11b ), OC(O)N(R ¹¹ R ^11a ), oxo (═O) where the ring is at least partially saturated, C _1-6 alkyl, C _{2-6 alkenyl, or C 2-6 alkynyl} , where C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ¹² which may be the same or different;
R ¹¹ , R ^11a , R ^11b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different;
each R ¹² is independently halogen, CN, C(O)OR ¹³ , OR ¹³ , C(O)R ¹³ , C(O)N(R ¹³ R ^13a ), S(O) ₂ N(R ¹³ R ^13a ), S(O)N(R ¹³ R ^13a ), S(O) ₂ R ¹³ , S(O)R ¹³ , N(R ¹³ )S(O) ₂ N(R ^13a R ^13b ), SR ¹³ , N(R ¹³ R ^13a ), NO ₂ , OC(O)R ¹³ , N(R ¹³ )C(O)R ^13a , N(R ¹³ )SO ₂ R ^13a , N(R ¹³ )S(O)R ^13a , N( ^R13 )C(O)N ^{(R13aR13b )} , ^N ( ^R13 )C(O) ^OR13a , or OC(O)N( ^R13R13a );
Also provided are: R ¹³ , R ^13a , R ^13b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different.

を有し、式中、
Ｘ^１は、Ｎ（Ｒ^ａ１）であり；
Ｒ^ａ１は、ＨもしくはＣ_１～４アルキルであり、ここで、Ｃ_１～４アルキルは、ハロゲン、ＯＨおよびＯ－Ｃ_１～３アルキルからなる群から選択される１個もしくはそれ以上の置換基で場合により置換されており、ここで、置換基は、同じもしくは異なり、好ましくは、Ｒ^ａ１はＨであり；
Ｒ^ａ２、Ｒ^ａ３、Ｒ^ａ４、Ｒ^ａ５、Ｒ^ａ６は、Ｈであるか；
またはＲ^ａ１ならびにＲ^ａ２およびＲ^ａ３の１つは、メチレンもしくはエチレン基を形成するか；
またはＲ^ａ１およびＲ^ａ６は、エチレン基を形成し；
Ａ^１は、Ｃ_５シクロアルキレン、Ｃ_５シクロアルケニレン、または窒素環原子含有５員ヘテロシクレンであり、ここで、Ａ^１は、同じまたは異なる１つまたはそれ以上のＲ^４で場合により置換されており；
各Ｒ^４は独立して、ハロゲン、ＣＮ、ＯＲ^５、環が少なくとも部分的に飽和されているオキソ（＝Ｏ）、またはＣ_１～６アルキルであり、ここで、Ｃ_１～６アルキルは、同じまたは異なる１つまたはそれ以上のハロゲンで場合により置換されており；
Ｒ^５は、ＨまたはＣ_１～６アルキルであり、ここで、Ｃ_１～６アルキルは、同じまたは異なる１つまたはそれ以上のハロゲンで場合により置換されており；
Ａ^２は、フェニル、または５員から６員の芳香族ヘテロシクリルであり、ここで、Ａ^２は、同じまたは異なる１つまたはそれ以上のＲ^６で場合により置換されており；
各Ｒ^６は独立して、ＯＨ、Ｏ（Ｃ_１～６アルキル）、ハロゲン、ＣＮ、シクロプロピル、Ｃ_１～６アルキル、Ｃ_２～６アルケニルもしくはＣ_２～６アルキニルであり、ここで、シクロプロピル、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルは、同じもしくは異なる１つもしくはそれ以上のハロゲンで場合により置換されているか；または
２つのＲ^６は、接続されることで、それらが付着されている原子と一緒に、環Ａ^２ｂを形成し；
Ａ^２ｂは、フェニル；Ｃ_３～７シクロアルキル；または３員から７員のヘテロシクリルであり、ここで、Ａ^２ｂは、同じまたは異なる１つまたはそれ以上のＲ^７で場合により置換されており；
各Ｒ^７は独立して、Ｃ_１～６アルキル、Ｃ_２～６アルケニルまたはＣ_２～６アルキニルであり、ここで、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルは、同じまたは異なる１つまたはそれ以上のハロゲンで場合により置換されており；
Ｒ^１は、ＨまたはＣ_１～４アルキル、好ましくはＨであり、ここで、Ｃ_１～４アルキルは、同じまたは異なる１つまたはそれ以上のハロゲンで場合により置換されており；
Ｒ^２は、ＨもしくはＣ_１～４アルキルであり、ここで、Ｃ_１～４アルキルは、同じもしくは異なる１つもしくはそれ以上のハロゲンで場合により置換されており；
Ｒ^３は、Ａ^３、Ｃ_１～６アルキル、Ｃ_２～６アルケニルもしくはＣ_２～６アルキニルであり、ここで、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルは、同じもしくは異なる１つもしくはそれ以上のＲ^８で場合により置換されているか；または
Ｒ^２およびＲ^３は、接続されることで、７員から１２員のヘテロビシクリルを形成し、ここで、７員から１２員のヘテロビシクリルは、同じもしくは異なる１つもしくはそれ以上のＲ^１０で場合により置換されており；
各Ｒ^８は独立して、ハロゲン；ＣＮ、Ｃ（Ｏ）ＯＲ^９、ＯＲ^９、Ｃ（Ｏ）Ｒ^９、Ｃ（Ｏ）Ｎ（Ｒ^９Ｒ^９ａ）、Ｓ（Ｏ）_２Ｎ（Ｒ^９Ｒ^９ａ）、Ｓ（Ｏ）Ｎ（Ｒ^９Ｒ^９ａ）、Ｓ（Ｏ）_２Ｒ^９、Ｓ（Ｏ）Ｒ^９、Ｎ（Ｒ^９）Ｓ（Ｏ）_２Ｎ（Ｒ^９ａＲ^９ｂ）、ＳＲ^９、Ｎ（Ｒ^９Ｒ^９ａ）、ＮＯ_２、ＯＣ（Ｏ）Ｒ^９、Ｎ（Ｒ^９）Ｃ（Ｏ）Ｒ^９ａ、Ｎ（Ｒ^９）ＳＯ_２Ｒ^９ａ、Ｎ（Ｒ^９）Ｓ（Ｏ）Ｒ^９ａ、Ｎ（Ｒ^９）Ｃ（Ｏ）Ｎ（Ｒ^９ａＲ^９ｂ）、Ｎ（Ｒ^９）Ｃ（Ｏ）ＯＲ^９ａ、ＯＣ（Ｏ）Ｎ（Ｒ^９Ｒ^９ａ）、またはＡ^３であり；
Ｒ^９、Ｒ^９ａ、Ｒ^９ｂは、Ｈ、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルからなる群から独立して選択され、ここで、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルは、同じまたは異なる１つまたはそれ以上のハロゲンで場合により置換されており；
各Ａ^３は独立して、フェニル、ナフチル、Ｃ_３～７シクロアルキル、３員から７員のヘテロシクリル、または７員から１２員のヘテロビシクリルであり、ここで、Ａ^３は、同じまたは異なる１つまたはそれ以上のＲ^１０で場合により置換されており；
各Ｒ^１０は独立して、ハロゲン、ＣＮ、Ｃ（Ｏ）ＯＲ^１１、ＯＲ^１１、Ｃ（Ｏ）Ｒ^１１、Ｃ（Ｏ）Ｎ（Ｒ^１１Ｒ^１１ａ）、Ｓ（Ｏ）_２Ｎ（Ｒ^１１Ｒ^１１ａ）、Ｓ（Ｏ）Ｎ（Ｒ^１１Ｒ^１１ａ）、Ｓ（Ｏ）_２Ｒ^１１、Ｓ（Ｏ）Ｒ^１１、Ｎ（Ｒ^１１）Ｓ（Ｏ）_２Ｎ（Ｒ^１１ａＲ^１１ｂ）、ＳＲ^１１、Ｎ（Ｒ^１１Ｒ^１１ａ）、ＮＯ_２、ＯＣ（Ｏ）Ｒ^１１、Ｎ（Ｒ^１１）Ｃ（Ｏ）Ｒ^１１ａ、Ｎ（Ｒ^１１）Ｓ（Ｏ）_２Ｒ^１１ａ、Ｎ（Ｒ^１１）Ｓ（Ｏ）Ｒ^１１ａ、Ｎ（Ｒ^１１）Ｃ（Ｏ）ＯＲ^１１ａ、Ｎ（Ｒ^１１）Ｃ（Ｏ）Ｎ（Ｒ^１１ａＲ^１１ｂ）、ＯＣ（Ｏ）Ｎ（Ｒ^１１Ｒ^１１ａ）、環が少なくとも部分的に飽和されているオキソ（＝Ｏ）、Ｃ_１～６アルキル、Ｃ_２～６アルケニル、またはＣ_２～６アルキニルであり、ここで、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルは、同じまたは異なる１つまたはそれ以上のＲ^１２で場合により置換されており；
Ｒ^１１、Ｒ^１１ａ、Ｒ^１１ｂは、Ｈ、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルからなる群から独立して選択され、ここで、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルは、同じまたは異なる１つまたはそれ以上のハロゲンで場合により置換されており；
各Ｒ^１２は独立して、ハロゲン、ＣＮ、Ｃ（Ｏ）ＯＲ^１３、ＯＲ^１３、Ｃ（Ｏ）Ｒ^１３、Ｃ（Ｏ）Ｎ（Ｒ^１３Ｒ^１３ａ）、Ｓ（Ｏ）_２Ｎ（Ｒ^１３Ｒ^１３ａ）、Ｓ（Ｏ）Ｎ（Ｒ^１３Ｒ^１３ａ）、Ｓ（Ｏ）_２Ｒ^１３、Ｓ（Ｏ）Ｒ^１３、Ｎ（Ｒ^１３）Ｓ（Ｏ）_２Ｎ（Ｒ^１３ａＲ^１３ｂ）、ＳＲ^１３、Ｎ（Ｒ^１３Ｒ^１３ａ）、ＮＯ_２、ＯＣ（Ｏ）Ｒ^１３、Ｎ（Ｒ^１３）Ｃ（Ｏ）Ｒ^１３ａ、Ｎ（Ｒ^１３）ＳＯ_２Ｒ^１３ａ、Ｎ（Ｒ^１３）Ｓ（Ｏ）Ｒ^１３ａ、Ｎ（Ｒ^１３）Ｃ（Ｏ）Ｎ（Ｒ^１３ａＲ^１３ｂ）、Ｎ（Ｒ^１３）Ｃ（Ｏ）ＯＲ^１３ａ、またはＯＣ（Ｏ）Ｎ（Ｒ^１３Ｒ^１３ａ）であり；
Ｒ^１３、Ｒ^１３ａ、Ｒ^１３ｂは、Ｈ、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルからなる群から独立して選択され、ここで、Ｃ_１～６アルキル、Ｃ_２～６アルケニルおよびＣ_２～６アルキニルは、同じまたは異なる１つまたはそれ以上のハロゲンで場合により置換されている）も提供する。 The present invention also relates to preferred compounds of formula (I) or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein ^X1a is CH( ^R3 ), ^R2a and ^R2a are H, and thus the compound of formula (I-1)

wherein
^X1 is N(R ^a1 );
R ^a1 is H or C _1-4 alkyl, where C _1-4 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OH and O-C _1-3 alkyl, where the substituents are the same or different, preferably R ^a1 is H;
R ^a2 , R ^a3 , R ^a4 , R ^a5 , and R ^a6 are H;
or R ^a1 and one of R ^a2 and R ^a3 form a methylene or ethylene group;
Or R ^a1 and R ^a6 form an ethylene group;
A ¹ is a C ₅ cycloalkylene, a C ₅ cycloalkenylene, or a nitrogen ring atom-containing 5-membered heterocyclene, where A ¹ is optionally substituted with one or more R ⁴ , which may be the same or different;
each R ⁴ is independently halogen, CN, OR ⁵ , oxo (═O) whose ring is at least partially saturated, or C _1-6 alkyl, where C _1-6 alkyl is optionally substituted with one or more halogens which may be the same or different;
R ⁵ is H or C _1-6 alkyl, where C _1-6 alkyl is optionally substituted with one or more halogens which may be the same or different;
^A2 is phenyl or 5- to 6-membered aromatic heterocyclyl, where ^A2 is optionally substituted with one or more ^R6 , which may be the same or different;
Each R ⁶ is independently OH, O(C _1-6 alkyl), halogen, CN, cyclopropyl, C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, where cyclopropyl, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different; or two R ⁶ are connected to form, together with the atom to which they are attached, a ring A ^2b ;
A ^2b is phenyl; C _3-7 cycloalkyl; or 3- to 7-membered heterocyclyl, where A ^2b is optionally substituted with one or more R ⁷ , which may be the same or different;
each R ⁷ is independently a C _1-6 alkyl, a C _2-6 alkenyl, or a C _2-6 alkynyl, wherein the C _1-6 alkyl, the C _2-6 alkenyl, and the C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different;
R ¹ is H or C _1-4 alkyl, preferably H, where C _1-4 alkyl is optionally substituted with one or more halogens which may be the same or different;
^R2 is H or _C1-4 alkyl, where _C1-4 alkyl is optionally substituted with one or more halogens which may be the same or different;
R ³ is A ³ , C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, where the C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with one or more R ⁸ , which are the same or different; or R ² and R ³ are joined to form a 7- to 12-membered heterobicyclyl, where the 7- to 12-membered heterobicyclyl is optionally substituted with one or more R ¹⁰ , which are the same or different;
Each R ⁸ is independently halogen; CN, C(O)OR ⁹ , OR ⁹ , C(O)R ⁹ , C(O)N(R ⁹ R ^9a ), S(O) ₂ N(R ⁹ R ^9a ), S(O)N(R ⁹ R ^9a ), S(O) ₂ R ⁹ , S(O)R ⁹ , N(R ⁹ )S(O) ₂ N(R ^9a R ^9b ), SR ⁹ , N(R ⁹ R ^9a ), NO ₂ , OC(O)R ⁹ , N(R ⁹ )C(O)R ^9a , N(R ⁹ )SO ₂ R ^9a , N(R ⁹ )S(O)R ^9a , N(R ⁹ )C(O)N(R ^9a R ^9b ), N(R ⁹ )C(O)OR ^9a , OC(O)N(R ⁹ R ^9a ), or A ³ ;
R ⁹ , R ^9a , R ^9b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different;
each A ³ is independently phenyl, naphthyl, C _3-7 cycloalkyl, 3- to 7-membered heterocyclyl, or 7- to 12-membered heterobicyclyl, where A ³ is optionally substituted with one or more R ¹⁰ which are the same or different;
Each R ¹⁰ is independently halogen, CN, C(O)OR ¹¹ , OR ¹¹ , C(O)R ¹¹ , C(O)N(R ¹¹ R ^11a ), S(O) ₂ N(R ¹¹ R ^11a ), S(O)N(R ¹¹ R ^11a ), S(O) ₂ R ¹¹ , S(O)R ¹¹ , N(R ¹¹ )S(O) ₂ N(R ^11a R ^11b ), SR ¹¹ , N(R ¹¹ R ^11a ), NO ₂ , OC(O)R ¹¹ , N(R ¹¹ )C(O)R ^11a , N(R ¹¹ )S(O) ₂ R ^11a , N(R ¹¹ )S(O)R ^lla , N(R ¹¹ )C(O)OR ^11a , N(R ¹¹ )C(O)N(R ^11a R ^11b ), OC(O)N(R ¹¹ R ^11a ), oxo (═O) where the ring is at least partially saturated, C _1-6 alkyl, C _{2-6 alkenyl, or C 2-6 alkynyl} , where C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ¹² which may be the same or different;
R ¹¹ , R ^11a , R ^11b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different;
each R ¹² is independently halogen, CN, C(O)OR ¹³ , OR ¹³ , C(O)R ¹³ , C(O)N(R ¹³ R ^13a ), S(O) ₂ N(R ¹³ R ^13a ), S(O)N(R ¹³ R ^13a ), S(O) ₂ R ¹³ , S(O)R ¹³ , N(R ¹³ )S(O) ₂ N(R ^13a R ^13b ), SR ¹³ , N(R ¹³ R ^13a ), NO ₂ , OC(O)R ¹³ , N(R ¹³ )C(O)R ^13a , N(R ¹³ )SO ₂ R ^13a , N(R ¹³ )S(O)R ^13a , N( ^R13 )C(O)N ^{(R13aR13b )} , ^N ( ^R13 )C(O) ^OR13a , or OC(O)N( ^R13R13a );
Also provided are: R ¹³ , R ^13a , R ^13b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different.

Surprisingly, the disclosed example compounds according to the present invention have favorable physicochemical properties and/or selectivity that, in combination, help achieve beneficial therapeutic efficacy while limiting unintended reactivity.

A variable or substituent may be selected from a group of different variants, and when such a variable or substituent occurs more than once, each variant may be the same or different.

Within the meaning of this invention, the terms are used as follows:

The term "optionally substituted" means unsubstituted or substituted. In general, but without limitation, "one or more substituents" means one, two or three, preferably one or two substituents, more preferably one substituent. In general, these substituents can be the same or different. The term "one or more substituents" also means, for example, one, two, three, four or five, preferably one, two, three or four.

"Alkyl" means a straight or branched hydrocarbon chain. Each hydrogen of an alkyl carbon can be replaced by a substituent as further specified.

"Alkenyl" means a straight or branched hydrocarbon chain containing at least one carbon-carbon double bond. Each hydrogen of an alkenyl carbon can be replaced by a substituent as further specified.

"Alkynyl" means a straight or branched hydrocarbon chain containing at least one carbon-carbon triple bond. Each hydrogen of an alkynyl carbon can be replaced by a substituent as further specified.

"C _1-4 alkyl" means, for example, an alkyl chain having 1 to 4 carbon atoms at the end of the molecule, if present: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, or, when two parts of the molecule are linked by an alkyl group, for example, -CH ₂ -, -CH ₂ -CH ₂ -, -CH(CH ₃ )-, -CH ₂ -CH ₂ -CH ₂ -, -CH(C ₂ H ₅ )-, -C(CH ₃ ) ₂ -. Each hydrogen of a C _1-4 alkyl carbon can be replaced by a substituent as further specified. The term "C _1-3 alkyl" is defined accordingly.

"C _1-6 alkyl" means, for example, an alkyl chain having 1 to 6 carbon atoms at the end of the molecule, if present: C _1-4 alkyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, or, when two parts of the molecule are linked by an alkyl group, for example, -CH ₂ -, -CH ₂ -CH ₂ -, -CH(CH ₃ )-, -CH ₂ -CH ₂ -CH ₂ -, -CH(C ₂ H ₅ )-, -C(CH ₃ ) ₂ -. Each hydrogen of the _{C 1-6} alkyl carbon can be replaced by a substituent as further specified.

" _C2-6 alkenyl" means, for example, an alkenyl chain having from 2 to 6 carbon atoms at the ends of the molecule, if present: -CH= _CH2 , -CH=CH- _CH3 , _-CH2- CH= _CH2 , -CH=CH- _CH2 - _CH3 , -CH=CH-CH= _CH2 , or, if two parts of the molecule are linked by an alkenyl group, for example -CH=CH-. Each hydrogen of a _C2-6 alkenyl carbon can be replaced by a substituent as further specified.

" _C2-6 alkynyl" means, for example, an alkynyl chain having from 2 to 6 carbon atoms at the ends of the molecule, if present: -C≡CH, -CH2 _- C≡CH, _CH2 - _CH2- C≡CH, _CH2- C≡C- _CH3 , or, if two parts of the molecule are linked by an alkynyl group, for example, -C≡C-. Each hydrogen of a _C2-6 alkynyl carbon can be replaced by a substituent as further specified.

" _C3-7 cycloalkyl" or " _C3-7 cycloalkyl ring" means a cyclic alkyl chain having from 3 to 7 carbon atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl. Preferably, cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Each hydrogen of a cycloalkyl carbon may be replaced by a substituent as further specified herein. The term " _C3-5 cycloalkyl" or " _C3-5 cycloalkyl ring" is defined accordingly.

" _C5 cycloalkylene" refers to a divalent cycloalkyl having 5 carbon atoms, i.e., a divalent cyclopentyl ring.

" _C5 cycloalkenylene" refers to a divalent cycloalkenylene, i.e., a divalent cyclopentene or cyclopentadiene.

"C _4-12 bicycloalkyl" or "C _4-12 bicycloalkyl ring" means a bicyclic fused, bridged, or spiro alkyl chain having from 4 to 12 carbon atoms, e.g., hexahydroindane, octahydropentalene, bicyclic [2.2.1]heptane, or spiro(3.2)hexane. Each hydrogen of a bicycloalkyl carbon can be replaced by a substituent as further specified herein.

"Halogen" means fluoro, chloro, bromo or iodo. It is generally preferred that halogen is fluoro or chloro.

A "3- to 7-membered heterocyclyl" or "3- to 7-membered heterocycle" means a ring having 3, 4, 5, 6 or 7 ring atoms which may contain up to a maximum number of double bonds (aromatic or non-aromatic ring that is fully, partially or unsaturated), where at least one ring atom and up to four ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O) ₂ -), oxygen and nitrogen (including =N(O)-), and the ring is linked to the remainder of the molecule through a carbon or nitrogen atom. Examples for 3- to 7-membered heterocycles are aziridine, azetidine, oxetane, thietane, furan, thiophene, pyrrole, pyrroline, imidazole, imidazoline, pyrazole, pyrazoline, oxazole, oxazoline, isoxazole, isoxazoline, thiazole, thiazoline, isothiazole, isothiazolidine, thiadiazole, thiadiazoline, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, imidazolidine, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, thiadiazolidine, sulfolane, pyran, dihydropyran, tetrahydropyran, imidazolidine, pyridine, pyridazine, pyrazine, pyrimidine, piperazine, piperidine, morpholine, tetrazole, triazole, triazolidine, tetrazolidine, diazepane, azepine or homopiperazine. The term "5- to 6-membered heterocyclyl" or "5- to 6-membered heterocycle" is defined accordingly and includes 5- to 6-membered aromatic heterocyclyls or heterocycles. The term "5-membered heterocyclyl" or "5-membered heterocycle" is defined accordingly and includes 5-membered aromatic heterocyclyls or heterocycles.

The term "nitrogen ring atom-containing five-membered heterocyclene" refers to a divalent five-membered heterocycle in which at least one of the five ring atoms is a nitrogen atom and the ring is linked to the remainder of the molecule through a carbon or nitrogen atom.

"Saturated 4- to 7-membered heterocyclyl" or "saturated 4- to 7-membered heterocycle" means a fully saturated "4- to 7-membered heterocyclyl" or "4- to 7-membered heterocycle".

"4- to 7-membered at least partially saturated heterocyclyl" or "4- to 7-membered at least partially saturated heterocycle" means an at least partially saturated "4- to 7-membered heterocyclyl" or "4- to 7-membered heterocycle".

A "5- to 6-membered aromatic heterocyclyl" or a "5- to 6-membered aromatic heterocycle" means a heterocycle derived from cyclopentadienyl or benzene, in which at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O) ₂ -), oxygen and nitrogen (including =N(O)-). Examples of such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole, pyridine, pyrimidine, pyridazine, pyrazine, triazine.

A "5-membered aromatic heterocyclyl" or "5-membered aromatic heterocycle" means a heterocycle derived from cyclopentadienyl in which at least one carbon atom is replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O) ₂ -), oxygen and nitrogen (including =N(O)-). Examples of such heterocycles are furan, thiophene, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, thiadiazole, triazole, tetrazole.

A "7- to 12-membered heterobicyclyl" or "7- to 12-membered heterobicycle" means a two-ring heterocyclic system having from 7 to 12 ring atoms, where at least one ring atom is shared by both rings and the system can contain up to a maximum number of double bonds (aromatic or non-aromatic rings that are fully, partially or unsaturated), where at least one ring atom and up to six ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O) ₂ -), oxygen and nitrogen (including =N(O)-), and the ring is linked to the remainder of the molecule via a carbon or nitrogen atom. Examples for 7- to 12-membered heterobicycles are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, decahydroisoquinoline, tetrahydroisoquinoline, dihydroisoquinoline, benzazepine, purine or pteridine. The term 7- to 12-membered heterobicycle also includes spiro structures of two rings such as 6-oxa-2-azaspiro[3,4]octane, 2-oxa-6-azaspiro[3.3]heptan-6-yl or 2,6-diazaspiro[3.3]heptan-6-yl, or bridged heterocycles such as 8-aza-bicyclo[3.2.1]octane or 2,5-diazabicyclo[2.2.2]octan-2-yl or 3,8-diazabicyclo[3.2.1]octane.

"Saturated 7- to 12-membered heterobicyclyl" or "saturated 7- to 12-membered heterobicycle" means a fully saturated "7- to 12-membered heterobicyclyl" or "7- to 12-membered heterobicycle".

"7- to 12-membered at least partially saturated heterobicyclyl" or "7- to 12-membered at least partially saturated heterobicycle" means an at least partially saturated "7- to 12-membered heterobicyclyl" or "7- to 12-membered heterobicycle".

A "9- to 11-membered aromatic heterobicyclyl" or "9- to 11-membered aromatic heterobicycle" means a two-ring heterocyclic system, where at least one ring is aromatic, the heterocyclic ring system having 9 to 11 ring atoms, where two ring atoms are shared by both rings and the system may contain up to a maximum number of double bonds (fully or partially aromatic), where at least one ring atom and up to six ring atoms are replaced by a heteroatom selected from the group consisting of sulfur (including -S(O)-, -S(O) ₂ -), oxygen and nitrogen (including =N(O)-), and where the ring is linked to the remainder of the molecule via a carbon or nitrogen atom. Examples for 9- to 11-membered aromatic heterobicycles are indole, indoline, benzofuran, benzothiophene, benzoxazole, benzisoxazole, benzothiazole, benzisothiazole, benzimidazole, benzimidazoline, quinoline, quinazoline, dihydroquinazoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, tetrahydroisoquinoline, dihydro-isoquinoline, benzazepine, purine or pteridine. The terms "9- to 10-membered aromatic heterobicyclyl" or "9- to 10-membered aromatic heterobicycle" are defined accordingly.

Preferred compounds of formula (I) are those in which one or more of the residues contained therein have the meanings given above or below, all combinations of the preferred substituent definitions being subject of the present invention. For all preferred compounds of formula (I), the present invention also includes all tautomeric and stereoisomeric forms and mixtures thereof in all ratios, as well as their pharma- ceutically acceptable salts.

In preferred embodiments of the invention, the substituents described below have, independently, the following meanings. Therefore, one or more of these substituents can have the preferred or more preferred meanings given below.

Preferably, X ¹ is NH or N-C _1-4 alkyl, where C _1-4 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, and O-C _1-3 alkyl, where the substituents are the same or different; more preferably, X ¹ is NH, N(CH ₃ ), N(CH ₂ CH ₃ ) or N(CH ₂ CH ₂ OCH ₃ ); even more preferably NH or N(CH ₃ ); even more preferably NH.

Preferably, X ^1a is CH(R ^a3 ) or CH(R ^a3 )CH ₂ , more preferably CH(R ^a3 ).

Preferably, R ^a2 , R ^a3 are independently selected from the group consisting of H; OH; OC _1-4 alkyl; halogen; C _1-4 alkyl; and A ^2a ;
R ^a4 , R ^a5 , R ^a6 , and R ^a7 are independently selected from the group consisting of H; halogen; C _1-4 alkyl; and A ^2a , with the proviso that exactly one of R ^a2 , R ^a3 , R ^a4 , R ^a5 , R ^a6 , and R ^a7 is A ^2a ;
Or, R ^a5 and R ^a7 are connected to form an oxo group.

Preferably, R ^a2 , R ^a3 , R ^a4 , R ^a5 , R ^a6 , and R ^a7 are independently selected from the group consisting of H; halogen; C _1-4 alkyl; and A ^2a , with the proviso that only one of R ^a2 , R ^a3 , R ^a4 , R ^a5 , R ^a6 , and R ^a7 is A ^2a . More preferably, R ^a2 , R ^a3 , R ^a4 , R ^a5 , R ^a6 , and R ^a7 are H, or R ^a2 , R ^a3 , R ^a4 , and R ^a6 are H, and R ^a5 , R ^a7 are connected to form an oxo group. Even more preferably, R ^a2 , R ^a3 , R ^a4 , R ^a5 , R ^a6 , and R ^a7 are H.

Preferably, A ¹ is a nitrogen ring atom-containing 5-membered heterocyclene, A ¹ being optionally substituted with one or more R ⁴ , which may be the same or different.

More preferably, A ^{1 is a nitrogen ring atom-containing 5-membered heterocyclene selected from the group of divalent heterocycles consisting of oxadiazole, imidazole, imidazolidine, pyrazole and triazole, preferably oxadiazole, and A 1 is} optionally substituted with one or more R ⁴ , which may be the same or different.

Preferably, A ¹ is unsubstituted or substituted with one or two R ^{4 s} which are the same or different, preferably A ¹ is unsubstituted.

Preferably, R ⁴ is independently oxo (═O), halogen, CN, OR ⁵ , or C _1-6 alkyl, the ring of which is at least partially saturated, wherein the C _1-6 alkyl is optionally substituted with one or more halogens which may be the same or different.

Preferably, ^R4 is oxo, the ring being at least partially saturated.

であり、より好ましくは、Ａ^１は、

である。 Preferably, ^A1 is

and more preferably, A ¹ is

It is.

In one embodiment, ^A2 is ^R6a .

Preferably, R ^6a is OR ^6a1 .

In certain embodiments, R ^6a1 , R ^6a2 are independently selected from the group consisting of H; C _1-6 alkyl; C _{2-6 alkenyl; C 2-6 alkynyl; and A 2a, wherein C 1-6 alkyl} ^; _{C 2-6} alkenyl; and C _2-6 alkynyl are optionally substituted with one or more substituents selected from the group consisting of halogen; CN; OR ^6a3 ; and A ^2a , wherein the substituents are the same or different.

R ^6a1 is preferably A ^2a or _{C 1-6} alkyl optionally substituted with one or more halogen and/or one A ^2a and/or one OR ^6a3 . More preferably, R ^6a1 is C _1-6 alkyl optionally substituted with one or more F and/or one OR ^6a3 .

Preferably, R ^6a is C _1-6 alkyl optionally substituted with one or more halogens and/or one A ^2a and/or one OR ^6a3 . More preferably, R ^6a is C _1-6 alkyl optionally substituted with one or more halogens and/or one OR ^6a3 .

In one preferred embodiment, R ^6a1 is unsubstituted C _4-6 alkyl; more preferably 3-methylbut-1-yl or n-butyl. In another preferred embodiment, R 6a1 is C _2-6 alkyl substituted with one or more halogens, which may be the same or different, preferably one or more fluoro; more preferably R ^6a1 is 3,3,3-trifluoropropyl, 2-methyl- ^3,3,3 -trifluoropropyl, 4,4,4-trifluorobut-2-yl, 2,2,3,3,3-pentafluoropropyl, 3,3-difluorobutyl or 3,3,3-trifluorobutyl. In another preferred embodiment, R ^6a1 is A ^2a , CH ₂ A ^2a , CH ₂ CH ₂ A ^2a , where A ^2a is unsubstituted or substituted with the same or different one or more halogens, preferably one or more fluoro; more preferably R ^6a1 is cyclobutyl, cyclopentyl, CH ₂ -cyclopropyl, CH ₂ -cyclobutyl, CH ₂ CH ₂ -cyclopropyl, where R ^6a1 is substituted with one or more F.

In a _particularly preferred embodiment, ^A2 is ^R6a , ^R6a _is ^OR6a1 _{, and} ^R6a1 is _{CH2CH2CF3 or CH2CH2OCF3} , preferably _{CH2CH2OCF3 .}

Preferably, R ^6a2 is H.

Preferably, R ^6a is OC _1-4 alkyl; OC _1-4 alkyl-OC _1-4 alkyl, where each C _1-4 alkyl is optionally substituted with one to three F; or OCH ₂ A ^2a .

In another embodiment, ^A2 is ^A2a .

Preferably, A ^2a is phenyl; C _3-7 cycloalkyl; or 3- to 7-membered heterocyclyl, where A ^2a is optionally substituted with one or more R ⁶ , which may be the same or different.

Preferably, A ^2a is phenyl, cyclobutyl, azetidinyl, pyrrolidinyl, or a 5- to 6-membered aromatic heterocyclyl, preferably pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, or 1,2,4-oxadiazolyl, where A ^2a is optionally substituted with one or more R ⁶ , which may be the same or different. More preferably, A ^2a is phenyl, or a 5- to 6-membered aromatic heterocyclyl, preferably pyridyl, pyrazinyl, pyridazinyl, pyrazolyl, or 1,2,4-oxadiazolyl, where A ^2a is optionally substituted with one or more R ⁶ , which may be the same or different.

More preferably, A ^2a is phenyl; cyclobutyl; pyridyl; azetidinyl; pyrazolyl; or pyrrolidinyl, wherein A ^2a is optionally substituted with one or more R ⁶ , which may be the same or different.

Preferably, A ^2a is a C _3-7 cycloalkyl, more preferably cyclobutyl, where A ^2a is optionally substituted with one or more R ⁶ which are the same or different.

Preferably, A ^2a is substituted with one or two R ⁶ which may be the same or different.

Preferably, ^R6 is independently F, Cl, _CF3 , _OCH3 , _OCF3 , _OCHF2 , _CH3 , _CH2CH3 , _CH2CF3 , O-cyclopropyl or cyclopropyl. More preferably, ^R6 is independently F, Cl, CF3, _OCH3 , _OCF3 , _{CH3 , CH2CH3} or _{cyclopropyl ,} preferably F, Cl, _CF3 , _OCH3 , _{CH3 , CH2CH3 or cyclopropyl} .

Preferably, ^R2 is _CH3 ; F; or H, more preferably H.

Preferably, R ⁹ , R ^9a , R ^9b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different, or one OH, or one OC _1-4 alkyl, or one A ³ .

Preferably, ^R3 is ^A3 .

Preferably, A ³ is phenyl, pyridyl, pyrazinyl, pyrimidazyl, cyclopropyl, cyclobutyl or cyclohexyl, where A ³ is optionally substituted with one or more of the same or different R ^10. More preferably, A ³ is phenyl, where A ³ is optionally substituted with one or more of the same or different R ¹⁰ .

Preferably, ^A3 is substituted with 1, 2 or 3, preferably 1 or 2 (more preferably 2) ^R10 which may be the same or different.

Preferably, ^R2 and ^R3 , together with the oxygen and the carbon atom to which they are attached, are joined to form a dihydrobenzopyran ring, wherein the ring is optionally substituted with one or more ^R10 , which may be the same or different, and preferably the ring is substituted with one or two ^R10 .

Preferably, ^R10 is independently F, Cl, Br, CN, _CHF2 , _CF3 , _OCH3 , _OCF3 , CH=O, _CH2OH or _CH3 ; preferably, F, Cl, Br, _CF3 , _OCF3 , CH=O, _CH2OH or _CH3 ; more preferably, F, Cl, _CF3 , CH=O, _CH2OH or _CH3 . More preferably, ^R10 is independently F or Cl.

Preferably, R ^a1 is H or C _1-4 alkyl, where C _1-4 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OH and O-C _1-3 alkyl, where the substituents are the same or different; preferably, R ^a1 is H; CH ₃ or CH ₂ CH ₃ ; more preferably, R ^a1 is H.

Compounds of formula (I) in which some or all of the radicals mentioned above have the preferred or more preferred meanings are also subject of the present invention.

Preferred specific compounds of the present invention are
tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamido tert-Butyl (2R,5S)-5-[2-(4-chlorophenoxy)propanamido]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl] N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]propanamide N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]-2-[(1s,3s)-3-(trifluoromethoxy)cyclobutoxy]acetamide tert-butyl(2R,5S)-5-{2-[(6-chloro-5-fluoropi 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide tert-butyl (2R,5S)-5-[2-(3,4-dichlorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3, 4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-[3-chloro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-[4-chloro-3-(difluoromethyl)phenoxy]-N-[ (3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-methylphenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(3,4-dimethyl phenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]-2-{[6-(trifluoromethyl)pyridin-3-yl]o 2-[3-methoxy-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-2-fluorophenoxy)acetamide]-2-[5-(3,3,3-trifluoro 2-(4-chloro-2-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(3-chloro-4-fluorophenoxy)-N-[(3S,6R)-6-[5 -(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-[4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(3,4-dichlorophenoxy)-N-[(3 S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-2,3-difluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3,5 2-[3-fluoro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine 2-(4-chloro-3-fluorophenoxy)-2,2-difluoro-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-[3-chloro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(3,4,5-trichlorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-bromophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-[3-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-cyanophenoxy)-N-[(3S,6R)-6-{5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide -[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-butyl(2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]pyrrolidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,5R)-5-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]pyrrolidin-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(6-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl]piperidine 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide rac-2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-oxopiperidin-3-yl]acetamide rac-2-(4-chloro-3-fluorophenoxy)-N-[(3R,6R)-2-oxo-6-{5-[(1s,3s)-3-(trifluoromethoxy)silyl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-3-yl]acetamide tert-butyl(2S,5R)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-{5-[3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide Setoamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-methylpiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-methylpiperidin-3-yl] 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethylpiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl] -1-ethylpiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-(2-methoxyethyl)piperidin-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5- [(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide N-[(3 S,6R)-6-[5-(5-chloro-1-methyl-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[6-(trifluoromethyl)pyridin-3-yl]-1,3,4-oxadiazol-2 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(5-chloropyridin-2-yl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chloro-3-fluorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethoxy)propyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5 -[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide te rt-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazol 2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(difluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(trifluoromethoxy)methyl tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)- N-[(3S,6R)-6-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(4,4,4-trifluorobutan-2-yl)oxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3-difluorobutoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(2,2-difluorocyclopropyl)methoxy]-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide }piperidin-3-yl]acetamide N-[(3S,6R)-6-(5-butoxy-1,3,4-oxadiazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(3,3-difluorocyclopentyl)oxy]-1,3,4-oxadiazol-2-yl 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2-cyclopropylethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-methylbutoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(2,2-difluorocyclobutyl)methoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3-difluorocyclobutoxy)-1, 3,4-Oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2,2,3,3,3-pentafluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4,4 ,4-trifluorobutoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(difluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-3- 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2 -(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(pentyloxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-methoxypropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4- 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2-ethoxyethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide (4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2-cyclobutoxyethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl ]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(4,4-difluoropentyl)oxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl }piperidin-3-yl]acetamide N-[(3S,6R)-6-[5-(2-cyclopropoxyethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]-2-(3,4-dichlorophenoxy)acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(2,2-difluorocyclopropoxy)ethoxy]-1,3,4- 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{[2-(trifluoromethyl)cyclopropyl]methoxy}-1,3,4-oxadiazol-2-yl)piperidin-3-yl]acetamide tert-butyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamide]-2-{5-[3-(trifluoromethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-( 4-Chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(2,2,2-trifluoroethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-methyl-3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-methyl-3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{methyl 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-cyclopropoxyazetidin-1-yl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide ... tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-2-yl}piperidin-3-yl]acetamido 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-3-yl}piperidin-3-yl]acetamide tert-butyl(2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl )oxy]acetamide}-2-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-[(3S,6R)-6-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide 2-(4-chloro-3 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{2-[(1R)-2,2-difluorocyclopropoxy]ethoxy}-1,3,4-oxadiazole 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{2-[(1S)-2,2-difluorocyclopropoxy]ethoxy}-1,3,4-oxadiazol-2-yl)piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1r,3r) -3-cyclopropoxycyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-cyclopropoxycyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide (2R)-2-(4-chlorophenoxy) -N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]propanamide (2S)-2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]propanamide 2-(4-chloro- 3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-oxopiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-oxopiperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(3S)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1 ,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]-2-[4-(trifluoromethyl)phenoxy]acetamide 2-[3-chloro-4-(difluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide and 2-[3-fluoro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide.

Where tautomerism, e.g. keto-enol tautomerism, of the compounds of formula (I) may occur, the individual forms, e.g. keto and enol forms, are included separately and together as mixtures in any ratio. The same applies to stereoisomers, e.g. enantiomers, cis/trans isomers, conformers, etc.

In particular, when enantiomeric or diastereomeric forms are indicated in a compound according to formula (I), each pure form separately and any mixture of at least two of the pure forms in any ratio are encompassed by formula (I) and are subject of the present invention.

に示されている通りの相対的立体配置を有する式（Ｉ）の化合物、またはその薬学的に許容される塩、溶媒和物、水和物、互変異性体もしくは立体異性体である。 Preferred compounds are of formula (Ia)

or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof.

Isotopically labeled compounds of formula (I) are also within the scope of the present invention. Methods for isotopic labeling are known in the art. Preferred isotopes are those of the elements H, C, N, O and S. Solvates and hydrates of compounds of formula (I) are also within the scope of the present invention.

If desired, isomers can be separated by methods well known in the art, for example by liquid chromatography. The same applies for enantiomers, for example by using chiral stationary phases. Additionally, enantiomers can be isolated by converting them into diastereomers, i.e., coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of formula (I) can be obtained from a stereoselective synthesis using optically pure starting materials, reagents and/or catalysts.

In the case where the compounds according to formula (I) contain one or more acidic or basic groups, the present invention also includes their corresponding pharma- ceutically or toxicologically acceptable salts, in particular their pharma- ceutical usable salts. Thus, compounds of formula (I) containing acidic groups can be used according to the present invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts, or salts with ammonia or organic amines, such as ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of formula (I) containing one or more basic groups, i.e. groups that can be protonated, can be present and used according to the present invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to those skilled in the art. If the compounds of formula (I) contain simultaneously acidic and basic groups in the molecule, the invention also includes inner salts or betaines (zwitterions) in addition to the salt forms described. The respective salts according to formula (I) can be obtained by the customary methods known to those skilled in the art, such as, for example, by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts. The present invention also includes all salts of compounds of formula (I) which are not directly suitable for use in medicines due to their low physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

As shown below, the compounds of the present invention are believed to be suitable for modulating the integrated stress response pathway.

The integrated stress response (ISR) is a cellular stress response common to all eukaryotes (1). Dysregulation of ISR signaling has important pathological consequences leading to inflammation, viral infections, diabetes, cancer and neurodegenerative diseases, among others.

ISR is a common factor in different types of cellular stress that results in phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2alpha) on serine 51, leading to the suppression of normal protein synthesis and the expression of stress-responsive genes (2). In mammalian cells, the phosphorylation is carried out by a family of four eIF2alpha kinases, each of which responds to distinct environmental and physiological stresses: PKR-like ER kinase (PERK), double-stranded RNA-dependent protein kinase (PKR), heme-regulated eIF2alpha kinase (HRI), and general control non-derepressible 2 (GCN2) (3).

eIF2alpha, together with eIF2beta and eIF2gamma, forms the eIF2 complex, a key player in normal initiation of mRNA translation (4). The eIF2 complex binds GTP and Met- _tRNAi to form the ternary complex (eIF2-GTP-Met-tRNAi ₎ that is recruited by the ribosome for translation initiation (5, 6).

eIF2B is a heterodecamer complex consisting of five subunits (alpha, beta, gamma, delta, and epsilon) that in duplicate form a GEF-active decamer (7).

In response to ISR activation, phosphorylated eIF2alpha inhibits eIF2B-mediated exchange of GDP with GTP, resulting in reduced ternary complex formation and therefore inhibition of translation of normal mRNAs characterized by ribosome binding to the 5'AUG start codon (8). Under these conditions of reduced ternary complex abundance, translation of some specific mRNAs, including the mRNA encoding the transcription factor ATF4, is activated through a mechanism involving altered translation of upstream ORFs (uORFs) (7, 9, 10). Under these conditions of reduced ternary complex abundance, translation of some specific mRNAs, including the mRNA encoding the transcription factor ATF4, is activated through a mechanism involving altered translation of upstream ORFs (uORFs) (7, 9, 10). These mRNAs typically contain one or more uORFs that function normally in non-stressed cells to restrict ribosome flow to the main coding ORF. For example, during normal conditions, uORFs in the 5'UTR of ATF occupy ribosomes and prevent translation of the coding sequence of ATF4. However, during stress conditions, i.e., under conditions of reduced ternary complex formation, the probability that ribosomes will scan past these upstream ORFs and begin translation at the ATF4-encoding ORF is increased. ATF4 and other stress response factors expressed in this way subsequently govern the expression of an array of further stress response genes. The acute phase consists in the expression of proteins aimed at restoring homeostasis, while the chronic phase leads to the expression of pro-apoptotic factors (1, 11, 12, 13).

Upregulation of markers of ISR signaling has been demonstrated in a variety of conditions, among these cancers and neurodegenerative diseases. In cancer, ER stress-regulated translation increases resistance to hypoxic conditions and promotes tumor growth (14, 15, 16), and genetically targeted deletion of PERK has been shown to retard the growth of tumors derived from transformed PERK ^−/− mouse embryonic fibroblasts (14, 17). Furthermore, a recent report provided proof of concept that activators of eIF2B are effective in treating an aggressive form of metastatic prostate cancer using patient-derived xenograft modeling in mice (28). Taken together, prevention of cytoprotective ISR signaling may represent an effective antiproliferative strategy for the treatment of at least some forms of cancer.

Furthermore, modulation of ISR signaling could prove effective in preserving synaptic function and reducing neuronal attenuation, as well as in neurodegenerative diseases characterized by activation of the misfolded and unfolded protein response (UPR), such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer's disease (AD), Parkinson's disease (PD) and Jakob Creutzfeldt (prion) disease (18, 19, 20). There are examples of neurodegenerative diseases in which it has been shown that pharmacological as well as genetic inhibition of ISR signaling can normalize protein translation levels, rescue synaptic function and prevent neuronal loss, as for prion diseases (21). Specifically, reduction of the levels of phosphorylated eIF2alpha by overexpression of a phosphatase that controls phosphorylated eIF2alpha levels increased survival time of prion-infected mice, whereas maintained eIF2alpha phosphorylation reduced survival time (22).

Furthermore, direct evidence for the importance of controlling protein expression levels for proper brain function exists in the form of rare genetic diseases that affect the function of eIF2 and eIF2B. Mutations in eIF2 gamma that disrupt the eIF2 complex integrity and therefore result in a reduction in normal protein expression levels lead to intellectual disability syndrome (ID) (23). Partial loss of function mutations in subunits of eIF2B have been shown to be the cause of rare leukodystrophic vanishing white matter disease (VWMD) (24, 25). Specifically, stabilization of eIF2B partial loss of function in VWMD mouse models with small molecules related to ISRIB has been shown to reduce ISR markers and improve functional as well as pathological endpoints (26, 27).

The present invention provides compounds of the present invention in free form or in pharma- ceutically acceptable salt form, or in the form of a solvate, hydrate, tautomer or stereoisomer, for use in the treatment of the diseases or disorders described herein. The same applies to pharmaceutical compositions of the present invention.

Thus, one aspect of the invention is a compound of the invention or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, for use as a medicament as described above. The same applies to a pharmaceutical composition of the invention.

The described treatment methods can be applied to mammals such as dogs, cats, cows, horses, rabbits, monkeys and humans. Preferably, the mammalian patient is a human patient.

The present invention therefore provides a compound of the present invention, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of one or more diseases or disorders associated with the integrated stress response.

A further aspect of the invention is a compound of the invention, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof, for use in a method for treating or preventing one or more disorders or diseases associated with the integrated stress response.

A further aspect of the invention is the use of a compound of the invention, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment or prevention of one or more disorders or diseases associated with the integrated stress response.

Yet another aspect of the invention is a method for treating, controlling, delaying or preventing one or more diseases or disorders associated with the integrated stress response in a mammalian patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound of the invention, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof.

The present invention provides a compound of the present invention, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of one or more of the diseases or disorders described below.

A further aspect of the invention is a compound of the invention, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof, for use in a method of treating or preventing one or more of the disorders or diseases described below.

A further aspect of the invention is the use of a compound of the invention, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment or prevention of one or more of the disorders or diseases described below.

Yet another aspect of the present invention is a method for treating, controlling, delaying or preventing in a mammalian patient in need of treatment one or more of the diseases or disorders described below, comprising administering to said patient a therapeutically effective amount of a compound of the present invention, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition thereof.

The disease or disorder includes, but is not limited to, a disease selected from the group consisting of leukodystrophies, intellectual disability syndromes, neurodegenerative diseases and disorders, neoplastic diseases, infectious diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, ocular diseases, as well as organ fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lungs, chronic and acute diseases of the kidneys, myocardial infarction, cardiovascular diseases, arrhythmias, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain.

Leukodystrophies Examples of leukodystrophies include, but are not limited to, vanishing white matter disease with CNS hypomyelination (VWMD) and childhood ataxia (e.g., associated with defects in the function of eIF2 or components in signaling or signaling pathways including eIF2).

Intellectual disability syndrome Intellectual disability specifically refers to a condition in which a person has certain limitations in intellectual functions, such as communicating, caring for oneself, and/or has a deficit in social skills. Intellectual disability syndrome includes, but is not limited to, intellectual disability conditions associated with a deficit in the function of eIF2 or components in signal transduction or signal transduction pathways, including eIF2.

Neurodegenerative Diseases/Disorders Examples of neurodegenerative diseases and disorders include, but are not limited to, Alexander disease, Alper's disease, Alzheimer's disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), bovine spongiform encephalopathy (BSE), Canavan disease, Cockayne syndrome, corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Straussler-Scheinker syndrome, Huntington's disease, HIV-associated dementia, Kennedy disease, Krabbe disease, Coutts-Barr syndrome, and others. Lew, Lewy body dementia, Machado-Joseph disease (Spinocerebellar degeneration type 3), multiple sclerosis, multiple system atrophy, narcolepsy, neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher disease, Pick's disease, primary lateral sclerosis, prion diseases, progressive supranuclear palsy, Refsum's disease, Sandhoff's disease, Schilder's disease, subacute combined degeneration of the spinal cord secondary to pernicious anemia, schizophrenia, spinocerebellar degeneration (multiple types with variable features), spinal muscular atrophy, Steele-Richardson-Olszewski disease, fistula spinalis, and tauopathies.

In particular, the neurodegenerative disease or disorder is selected from the group consisting of Alzheimer's disease, Parkinson's disease and amyotrophic lateral sclerosis.

Neoplastic Diseases Neoplastic diseases can be understood in the broadest sense as any tissue resulting from misregulation of cell growth. In many cases, a neoplasm leads to at least a bulky tissue mass, possibly innervated by blood vessels. It may or may not include the formation of one or more metastases/metastases. The neoplastic disease of the present invention may be any neoplasm as classified by the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) classification C00-D48.

By way of example, a neoplastic disease according to the invention may be the presence of one or more malignant neoplasm(s) (tumors) (ICD-10 classifications C00-C97), may be the presence of one or more in situ neoplasm(s) (ICD-10 classifications D00-D09), may be the presence of one or more benign neoplasm(s) (ICD-10 classifications D10-D36), or may be the presence of one or more neoplasm(s) of indeterminate or unknown behavior (ICD-10 classifications D37-D48). Preferably, a neoplastic disease according to the invention refers to the presence of one or more malignant neoplasm(s), i.e. malignant neoplasm (ICD-10 classifications C00-C97).

In a more preferred embodiment, the neoplastic disease is cancer.

Cancer can be understood in its broadest sense as any malignant neoplastic disease, i.e., the presence of one or more malignant neoplasms in a patient. Cancer can be a solid or hematological malignancy. Contemplated herein are, without limitation, leukemias, lymphomas, carcinomas and sarcomas.

In particular, neoplastic diseases such as cancer characterized by upregulated ISR markers are included herein.

Illustrative cancers include, but are not limited to, thyroid cancer, cancer of the endocrine system, pancreatic cancer, brain cancer (e.g., glioblastoma multiforme, glioma), breast cancer (e.g., ER positive, ER negative, chemotherapy resistant, Herceptin resistant, HER2 positive, doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobular carcinoma, primary, metastatic), cervical cancer, ovarian cancer, uterine cancer, colon cancer, head and neck cancer, liver cancer (e.g., hepatocellular carcinoma), kidney cancer, lung cancer (e.g., non-small cell lung carcinoma, squamous cell lung carcinoma, adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma, carcinoid, sarcoma), colon cancer, esophageal cancer, gastric cancer, bladder cancer, bone cancer, stomach cancer, prostate cancer, and skin cancer (e.g., melanoma).

Further examples include, but are not limited to, myeloma, leukemia, mesothelioma, and sarcoma.

Additional examples include, but are not limited to, medulloblastoma, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulinoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphoma, genitourinary cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical carcinoma, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, Paget's disease of the nipple, phyllodes tumor, lobular carcinoma, ductal carcinoma, carcinoma of pancreatic stellate cells, and carcinoma of hepatic stellate cells.

Illustrative leukemias include, but are not limited to, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, nonleukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonic leukemia, eosinophilic leukemia, Gross leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, These include leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphotropic leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myelogranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasma cell leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling leukemia, stem cell leukemia, subleukemic leukemia, and anaplastic cell leukemia.

Illustrative sarcomas include, but are not limited to, chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, liposarcoma, lipid sarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, choriocarcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, and fibrosarcoma. These include alveolar sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma.

Illustrative melanomas include, but are not limited to, acral lentigo melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungual melanoma, and superficial spreading melanoma.

Illustrative carcinomas include, but are not limited to, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, adenoid cystic carcinoma, adenomatous carcinoma, adrenal cortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, basaloid carcinoma, basal squamous cell carcinoma, bronchioloalveolar carcinoma, bronchogenic lung carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, choriocarcinoma, colloid carcinoma, comedocarcinoma, corpus carcinoma, cribriform carcinoma, armor carcinoma, skin carcinoma, cylindrical carcinoma, cylindrical cell carcinoma, ductal carcinoma, ductal carcinoma, compact carcinoma (carcinoma durum), embryonal carcinoma, encephalomyeloma, epidermoid carcinoma, epithelial adenoid carcinoma, exophytic carcinoma, preulcerative carcinoma (carcinoma ex ulcere), fibrous carcinoma, gelatinous carcinoma, gelatinous carcinoma, giant cell carcinoma, adenocarcinoma, granulosa cell carcinoma, hair matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, high renal form carcinoma, infantile embryonal carcinoma, carcinoma in situ, carcinoma in epidermis, carcinoma in situ carcinoma), Krompecher carcinoma, Kulchitzky cell carcinoma, large cell carcinoma, lenticular carcinoma, lenticular carcinoma, lipomatous carcinoma, lobular carcinoma, lymphoepithelial carcinoma, medullary carcinoma, melanotic carcinoma, soft carcinoma, mucinous carcinoma, mucinous adenocarcinoma (carcinoma muciparum), mucosal cell carcinoma (carcinoma mucocellulare), mucoepidermoid carcinoma, mucinous carcinoma, mucinous carcinoma, myxomatous carcinoma (carcinoma myxomatodes), nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, squamous cell carcinoma, pasty carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, Schneiderian carcinoma, scirrhous carcinoma, scrotal carcinoma, signet ring cell carcinoma, simplex carcinoma, small cell carcinoma, solenoid carcinoma, globular cell carcinoma, spindle cell carcinoma, cavernous carcinoma, squamous cell carcinoma, linear carcinoma, angiectatic carcinoma, telangiectatic carcinoma, transitional cell carcinoma, nodular carcinoma, tubular carcinoma, nodular carcinoma, verrucous carcinoma, and choriocarcinoma.

Examples of infectious diseases include, but are not limited to, infections caused by viruses (such as infections caused by HIV-1: human immunodeficiency virus type 1; IAV: influenza A virus; HCV: hepatitis C virus; DENV: dengue virus; ASFV: African swine fever virus; EBV: Epstein-Barr virus; HSV1: herpes simplex virus 1; CHIKV: chikungunya virus; HCMV: human cytomegalovirus; SARS-CoV: severe acute respiratory syndrome coronavirus; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2), and infections caused by bacteria (such as infections caused by Legionella, Brucella, Simkania, Chlamydia, Helicobacter, and Campylobacter).

Inflammatory Diseases Examples of inflammatory diseases include, but are not limited to, postoperative cognitive dysfunction (decline in cognitive function after surgery), traumatic brain injury, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, type 1 diabetes mellitus, Guillain-Barre syndrome, Hashimoto's encephalitis, Hashimoto's thyroiditis, ankylosing spondylitis, psoriasis, Sjogren's syndrome, vasculitis, glomerular Nephritis, autoimmune thyroiditis, Behcet's disease, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves' ophthalmopathy, inflammatory bowel disease, Addison's disease, vitiligo, asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, sarcoidosis, transplant rejection, interstitial cystitis, atherosclerosis, and atopic dermatitis.

Musculoskeletal Disorders Examples of musculoskeletal disorders include, but are not limited to, muscular dystrophies, multiple sclerosis, Friedrich's ataxia, muscle wasting disorders (e.g., muscle atrophy, sarcopenia, cachexia), inclusion body myopathy, progressive muscular atrophy, motor neuron disease, carpal tunnel syndrome, epicondylitis, tendonitis, back pain, muscle pain, muscle soreness, repetitive strain disorders, and paralysis.

Metabolic Diseases Examples of metabolic diseases include, but are not limited to, diabetes (especially type II diabetes), nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), Niemann-Pick disease, liver fibrosis, obesity, heart disease, atherosclerosis, arthritis, cystinosis, phenylketonuria, proliferative retinopathy, and Kearns-Sayre disease.

Ocular Diseases Examples of ocular diseases include, but are not limited to, edema or neovascularization associated with any occlusive or inflammatory retinal vascular disorder, e.g., iris neovascularization, neovascular glaucoma, pterygium, neovascularization of the glaucoma filtering bleb, conjunctival papilloma; choroidal neovascularization, e.g., neovascular age-related macular degeneration (AMD), myopia, pre-uveitis, trauma, or idiopathic; macular edema, e.g., post-surgical macular edema, secondary to uveitis including retinal and/or choroidal inflammation. macular edema due to diabetes, macular edema secondary to diabetes, and macular edema secondary to retinal vascular occlusive disease (i.e., branch and central retinal vein occlusion); retinal neovascularization due to diabetes, e.g., retinal vein occlusion, uveitis, ocular ischemic syndrome from carotid artery disease, ocular or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, or Eales disease; and genetic disorders, e.g., von Hippel-Lindau syndrome.

Additional Diseases Additional diseases include, but are not limited to, organ fibrosis (such as liver fibrosis, pulmonary fibrosis, or kidney fibrosis), chronic and acute diseases of the liver (such as fatty liver disease, or hepatic steatosis), chronic and acute diseases of the lungs, chronic and acute diseases of the kidneys, myocardial infarction, cardiovascular diseases, arrhythmias, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain.

Yet another aspect of the present invention is a pharmaceutical composition comprising at least one compound of the present invention or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, together with a pharma- ceutically acceptable carrier, optionally in combination with one or more other bioactive compounds or pharmaceutical compositions.

Preferably, the one or more biologically active compounds are modulators of the integrated stress response pathway other than a compound of formula (I).

"Pharmaceutical composition" means one or more active ingredients and one or more inactive ingredients that make up the carrier, as well as any product that results directly or indirectly from the combination, complexation or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Thus, the pharmaceutical composition of the present invention encompasses any composition made by admixing a compound of the present invention and a pharma- ceutical acceptable carrier.

The pharmaceutical compositions of the present invention may contain one or more additional compounds as active ingredients, such as a mixture of compounds of formula (I) in the composition or other modulators of the integrated stress response pathway.

The active ingredients may be contained in one or more different pharmaceutical compositions (combination pharmaceutical compositions).

The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.

The compositions include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation) or intranasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and the nature of the active ingredient. They are conveniently present in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

In practical use, the compounds of formula (I) can be combined as active ingredients in intimate admixture with pharmaceutical carriers according to conventional pharmaceutical compounding techniques. The carriers can take a wide variety of forms, depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing compositions for oral dosage forms, any of the usual pharmaceutical media, e.g., water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, etc., can be used in the case of oral liquid preparations, e.g., suspensions, elixirs, and solutions; or carriers, e.g., starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrants, etc., can be used in the case of oral solid preparations, such as powders, hard and soft capsules, and tablets, with solid oral preparations being preferred over liquid preparations.

Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets can be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of the active compound. The percentage of the active compound in these compositions can, of course, be varied and may conveniently be between about 2 percent and about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compound can also be administered intranasally, for example, as liquid drops or spray.

Tablets, pills, capsules, and the like may also contain binders such as gum tragacanth, acacia, corn starch, or gelatin; excipients such as dibasic calcium phosphate; disintegrants such as corn starch, potato starch, alginic acid; lubricants such as magnesium stearate; and sweeteners such as sucrose, lactose, or saccharin. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify the physical form of the dosage unit. For example, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

Compounds of formula (I) may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant, such as hydroxypropyl-cellulose. Dispersions can also be prepared in glycerin, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microbial organisms.

Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form should be sterile and fluid to the extent that easy syringability exists. It should be stable under the conditions of manufacture and storage and should be preserved against the contaminating action of microbial organisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerin, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be used to provide a mammal, particularly a human, with an effective dose of a compound of the present invention, such as oral, rectal, topical, parenteral, ocular, pulmonary, nasal, etc. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, etc. Preferably, the compound of formula (I) is administered orally.

The effective dosage of the active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosages may be readily ascertained by one skilled in the art.

Starting materials for the synthesis of preferred embodiments of the present invention can be purchased from commercially available sources such as Array, Sigma Aldrich, Acros, Fisher, Fluka, ABCR, etc., or can be synthesized using known methods by those of skill in the art.

In general, several methods are applicable to prepare the compounds of the present invention. In some cases, various strategies are combined. Sequential or convergent routes are used. Illustrative synthetic routes are described below.

I. Chemical synthesis Experimental procedure:
The following abbreviations and acronyms are used:
aq aqueous ACN acetonitrile AgOTf silver trifluoromethanesulfonate BrCN cyanogen bromide brine saturated solution of NaCl in water BnONH _2.HCl O-benzylhydroxylamine hydrochloride Boc tert-butoxycarbonyl Boc ₂ O di-tert-butyl dicarbonate
^t BuOK potassium tert-butoxideCSA (7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acidCV column volumeDAST N,N-diethylaminosulfur trifluorideDCM dichloromethaneDCE dichloroethaneDMSO dimethylsulfoxideDMSO-d _{hexadeuterated} dimethylsulfoxideDIPEA diisopropylethylamineDMF dimethylformamideDMAP N,N-dimethylpyridin-4-amineESI ⁺ positive ionization modeESI ⁻ negative ionization modeEtOAc ethyl acetateEtOH ethanolEt ₂ O diethyl etherH ₂ SO ₄ sulfateHATU 1-[bis(dimethylamino)methylidene]-1H-[1,2,3]triazolo[4,5-b]pyridin-1-ium 3-oxide hexafluorophosphateHCl Hydrochloric acid HPLC High performance liquid chromatography h hour(s)
IPA Isopropyl alcohol KHCO ₃ Potassium bicarbonate LiOH Lithium hydroxide LiOH.H ₂ O Lithium hydroxide hydrate m Multiplet m-CPBA 3-chlorobenzenecarboperoxoic acid MeOH Methanol MgSO ₄ Potassium sulfate min Minute MsOH Methanesulfonic acid mL Milliliter(s)
N ₂ nitrogen atmosphere Na ₂ SO ₃ sodium sulfite Na ₂ SO ₄ sodium sulfate NaBH ₄ sodium borohydride NaHCO ₃ sodium bicarbonate NH ₂ -NH 2.H _{2 O} hydrazine hydrate NH ₄ Cl ammonium chloride NiCl _{2.6H 2} O nickel(II) chloride hexahydrate NMM 4-methylmorpholine NMR nuclear magnetic resonance prep. preparative r.t. Room temperature Rochelle salt Potassium sodium L(+)-tartrate tetrahydrate RT retention time satd saturated SOCl ₂ thionyl chloride STAB sodium triacetoxyborohydride T3P propanephosphonic anhydride TsCl 4-methylbenzenesulfonyl chloride TCDI 1,1'-thiocarbonyldiimidazole THF tetrahydrofuran TFA 2,2,2-trifluoroacetic acid TFAA trifluoroacetic anhydride TMS-CF ₃ trimethyl(trifluoromethyl)silane TMSOI trimethylsulfoxonium iodide ZnBr ₂ zinc dibromide

Analytical LCMS conditions are as follows:

System 1 (S1): Acidic IPC Method (MS18 and MS19)
Analytical (MET/CR/1410) HPLC-MS was performed on a Shimadzu LCMS system using a Kinetex Core shell C18 column (2.1 mm x 50 mm, 5 μm; temperature: 40° C.) and a gradient of 5-100% B (A=0.1% formic acid in H ₂ O; B=0.1% formic acid in ACN) over 1.2 min, then 100% B for 0.1 min. A second gradient of 100-5% B was then applied at a flow rate of 1.2 mL/min with an injection volume of 3 μL over 0.01 min. UV spectra were recorded at 215 nm using an SPD-M20A photodiode array detector spectral range: 200-400 nm. Mass spectra were acquired using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

System 2 (S2): Acidic IPC method (MSQ2 and MSQ4):
Analytical (MET/uPLC/1704) uHPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEH™ C18 column (2.1 mm×50 mm, 1.7 μm; temperature 40° C.) and a gradient of 5-100% B (A=0.1% formic acid in H ₂ O: B=0.1% formic acid in ACN) over 1.1 min, then 100% B for 0.25 min. A second gradient of 100-5% B was then applied over 0.05 min and held at a flow rate of 0.9 mL/min with an injection volume of 1 μL for 0.1 min. UV spectra were recorded at 215 nm on a Waters Acquity PDA using a spectral range of 200-400 nm. Mass spectra were acquired using a Waters QDa. Data were integrated and reported using Waters MassLynx and OpenLynx software.

System 3 (S3): Basic IPC Method (MS16):
Analytical (MET/CR/1602) uHPLC-MS was performed on a Waters Acquity uPLC system using a Waters UPLC® BEH™ C18 column (2.1 mm×30 mm, 1.7 μm; temperature 40° C.) and a gradient of 5-100% B (A: 2 mM ammonium bicarbonate, buffered to pH 10, B: ACN) over 0.75 min, then 100% B for 0.1 min. A second gradient of 100-5% B was then applied over 0.05 min and held at a flow rate of 1 mL/min with an injection volume of 1 μL for 0.1 min. UV spectra were recorded at 215 nm on a Waters Acquity PDA using a spectral range of 200-400 nm. Mass spectra were acquired using a Waters Quattro Premier XE. Data were integrated and reported using Waters MassLynx and OpenLynx software.

System 4 (S4): Acidic Final Method (MSQ1 and MSQ2):
Analytical (MET/uPLC/AB101) uHPLC-MS was performed on a Waters Acquity uPLC system using a Phenomenex Kinetex-XB C18 column (2.1 mm x 100 mm, 1.7 μM; temperature: 40° C.) and a gradient of 5-100% B (A=0.1% formic acid in H ₂ O; B=0.1% formic acid in ACN) over 5.3 min, then 100% B for 0.5 min. A second gradient of 100-5% B was then applied over 0.02 min and held at a flow rate of 0.6 mL/min with an injection volume of 1 μL for 1.18 min. UV spectra were recorded at 215 nm using a Waters Acquity PDA detector spectral range: 200-400 nm. Mass spectra were acquired using a Waters SQD (MSQ1) or a Waters AcquityQDA (MSQ2). Data were integrated and reported using Waters MassLynx and OpenLynx software.

System 5 (S5): Acidic final method (MS18, MS19)
The Shimadzu LCMS system was run using a Waters Atlantis dC18 column (2.1 mm x 100 mm, 3 μm; temperature: 40° C.) and a gradient of 5-100% B over 5 min (A=0.1% in H ₂ O). Analytical (MET/CR/1416) HPLC-MS was performed using formic acid; B = 0.1% formic acid in ACN), followed by 100% B for 0.4 min. A second gradient of was then applied over 0.02 min and held at a flow rate of 0.6 mL/min with an injection volume of 3 μL for 1.58 min. SPD-M20A Photodiode Array Detector Spectral Range: 200- UV spectra were recorded at 215 nm using a 400 nm wavelength. Mass spectra were obtained using a 2010EV detector. Data were integrated and reported using Shimadzu LCMS-Solutions and PsiPort software.

System 6 (S6): Basic final method (MS16)
The elution was performed on a Waters Acquity uPLC system using a Waters UPLC® BEH™ C18 column (2.1 mm×100 mm, 1.7 μm column; temperature: 40° C.) and a gradient of 5 to 100% (A = 2 mM ammonium bicarbonate, buffered to pH 10; B = ACN) followed by analytical (MET/uHPLC/AB105) uPLC-MS using a gradient of 100% B in 0.5 min. A second gradient of .about.5% B was then applied over 0.02 min and held for 1.18 min at an injection volume of 1 μL and a flow rate of 0.6 mL/min. Waters Acquity photodiode array detector The spectral range: 200-400 nm was used and UV spectra were recorded at 215 nm. Mass spectra were obtained using a Waters Quattro Premier XE mass detector. Data were integrated and reported using Waters MassLynx and OpenLynx software.

The purification method is as follows:
Method 1: Acidic Initial Method Purification ( _P1 ) LC was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 100 mm, 10 μM; temperature: room temperature) and a gradient of 10-95% B (A = 0.1% formic acid in H2O; B = 0.1% formic acid in ACN) over 14.44 min, then 95% B in 2.11 min. A second gradient of 95-10% B was then applied at a flow rate of 40 mL/min with an injection volume of 1500 μL over 0.2 min. UV spectra were recorded at 215 nm using a Gilson detector.

Method 2: Acidic Standard Method Purification (P2) LC was performed on a Gilson LC system using a Waters Sunfire C18 column (30 mm x 10 mm, 10 μM; temperature: room temperature) and a gradient of 30-95% B (A = 0.1% formic acid in water; B = 0.1% formic acid in ACN) over 11.00 min, then 95% B in 2.10 min. A second gradient of 95-30% B was then applied at a flow rate of 40 mL/min with an injection volume of 1500 μL over 0.2 min. UV spectra were recorded at 215 nm using a Gilson detector.

Method 3: Basic Initial Method Purification (P3) LC was performed on a Gilson LC system using a Waters X-Bridge C18 column (30 mm x 100 mm, 10 μM; temperature: room temperature) and a gradient of 10-95% B (A = 0.2% NH ₄ OH in H ₂ O; B = 0.2% NH ₄ OH in ACN) over 14.44 min, then 95% B in 2.11 min. A second gradient of 95-10% B was then applied at a flow rate of 40 mL/min with an injection volume of 1500 μL over 0.2 min. UV spectra were recorded at 215 nm using a Gilson detector.

Method 4: Basic Standard Method Purification (P4) LC was performed on a Gilson LC system using a Waters X-Bridge C18 column (30 mm x 10 mm, 10 μM; temperature: room temperature) and a gradient of 30-95% B (A = 0.2% NH ₄ OH in water; B = 0.2% NH ₄ OH in ACN) over 11.00 min, then 95% B in 2.10 min. A second gradient of 95-30% B was then applied at a flow rate of 40 mL/min with an injection volume of 1500 μL over 0.21 min. UV spectra were recorded at 215 nm using a Gilson detector.

Method 5: Reverse Phase Chromatography using Acidic pH, Standard Elution Method Purification by FCC on reverse phase silica (acidic pH, standard elution method) was performed on a Biotage Isolera system using an appropriate SNAP C18 cartridge and 10% B over 1.7 CV (A=0.1% formic acid in H ₂ O; B=0.1% formic acid in ACN) followed by a gradient of 10-100% B over 19.5 CV and 100% B for 2 CV.

Method 6: Reverse-phase chromatography using basic pH, standard elution method Purification by FCC on reverse-phase silica (basic pH, standard elution method) was performed on a Biotage Isolera system using an appropriate SNAP C18 cartridge and 10% B over 1.7 CV (A=0.1% _NH3 in _H2O ; B=0.1% _NH3 in ACN) followed by a gradient of 10-100% B over 19.5 CV and 100% B for 2 CV.

Method 7: Reverse Phase Chromatography using Acidic pH, Standard Elution Method Purification by FCC on reverse phase silica (acidic pH, standard elution method) was performed on a Biotage Isolera system using an appropriate SNAP C18 cartridge and 10% B over 1.7 CV (A=0.1% TFA in H ₂ O; B=0.1% TFA in ACN) followed by a gradient of 10-100% B over 19.5 CV and 100% B for 2 CV.

Chiral separation methods:
Method C1
Purification method = 15% IPA: 85% heptane; Chiralcel OD-H, 20 x 250 mm, 5 μm at 18 mL/min. Sample diluents: MeOH, ACN.
Method C2
Purification method = EtOH with cellulose-4; 21.2 x 250 mm, 5 μm column at 9 mL/min. Sample diluents: EtOH, MeOH.
Method C3
Purification method = 15% IPA + 0.2% diethylamine: 85% CO ₂ ; Chiralpak AD-H, 10 x 250 mm, 5 μm at 15 mL/min. Sample diluents: IPA, MeOH, ACN.
Method C4
Purification method = MeOH + 0.2% diethylamine; Chiralpak AD-H, 20 x 250 mm, 5 μm at 7 mL/min. Sample diluent: MeOH.
Method C5
Purification method = 75:25 CO ₂ :MeOH; ChiralPak AD-H, 10 x 250 mm, 5 μm at 15 mL/min. Sample diluent: MeOH.
Method C6
Purification method = 15% MeOH, 85% CO ₂ ; Chiralcel OJ-H, 10 x 250 mm, 5 μm at 15 mL/min. Sample diluents: MeOH, IPA, ACN.
Method C7
Purification method = 80:20 heptane:EtOH; ChiralPak AD-H, 20 x 250 mm, 5 μm at 18 mL/min. Sample diluents: methanol, IPA.

NMR Conditions: Unless otherwise stated, ¹ H NMR spectra were recorded at 500 MHz, 400 MHz or 250 MHz on either a Bruker Avance III HD500 MHz, a Bruker Avance III HD400 MHz spectrometer or a Bruker Avance III HD250 MHz spectrometer, respectively. Chemical shifts δ are given in parts per million (ppm) and are referenced to the residual solvent peak. The following abbreviations are used to indicate multiplicity and general assignment: s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), ddd (doublet of doublets of doublets), dt (doublet of triplets), dq (doublet of quartets), hep (heptet), m (multiplet), pent (pentet), td (triplet of doublets), qd (quartet of doublets), app. (apparent) and br. (broad). Coupling constants J are given to the nearest 0.1 Hz.

General synthesis:
All compounds were synthesized with purity >95% unless otherwise specified. Chemical names were generated by Marvin Sketch, version 19.19.0 from ChemAxon Ltd.

Scheme for Route 1

ＤＭＳＯ（７５ｍＬ）を無水ＴＨＦ（６０ｍＬ）中のＴＭＳＯＩ（１２．８９ｇ、５８．３ｍｍｏｌ）および^ｔＢｕＯＫ（６．２７ｇ、５５．９ｍｍｏｌ）の溶液に添加し、混合物を室温で１時間の間撹拌した。反応混合物を－１２℃に冷却し、無水ＴＨＦ（３８ｍＬ）中のエチルＢｏｃ－Ｄ－ピログルタメート（１２．５ｇ、４８．６ｍｍｏｌ）の溶液を添加し、室温で１６時間の間撹拌した。反応混合物を飽和ＮＨ_４Ｃｌ水溶液（８０ｍＬ）、Ｈ_２Ｏ（１５ｍＬ）およびＥｔＯＡｃ（２００ｍＬ）で希釈し、有機層を単離し、ブラインで洗浄し、真空中でおよそ１００ｍＬに濃縮した。ＥｔＯＡｃ（６２ｍＬ）中のＢｎＯＮＨ_２・ＨＣｌ（８．１４ｇ、５１．０ｍｍｏｌ）の溶液を添加し、混合物を還流で２時間の間撹拌した。反応混合物を室温に冷却し、Ｈ_２Ｏおよびブラインで洗浄し、有機層を真空中で濃縮することで、標題化合物が（８５％の純度、１９．５ｇ、４０．１ｍｍｏｌ、８３％の収率）無色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) δ 7.16 - 7.33 (m, 5H), 5.01 - 5.06 (m, 2H), 3.95 - 4.30 (m, 5H), 2.32 - 2.50 (m, 2H), 1.98 - 2.13 (m, 1H), 1.75 - 1.92 (m, 1H),1.30 - 1.40 (m, 9H), 1.12 - 1.24 (m, 3H), Step 1. a: Ethyl (2R)-5-[(benzyloxy)imino]-2-{[(tert-butoxy)carbonyl]amino}-6-chlorohexanoate

DMSO (75 mL) was added to a solution of TMSOI (12.89 g, 58.3 mmol) and ^t BuOK (6.27 g, 55.9 mmol) in anhydrous THF (60 mL) and the mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to −12° C. and a solution of ethyl Boc-D-pyroglutamate (12.5 g, 48.6 mmol) in anhydrous THF (38 mL) was added and stirred at room temperature for 16 h. The reaction mixture was diluted with saturated aqueous NH ₄ Cl (80 mL), H ₂ O (15 mL) and EtOAc (200 mL) and the organic layer was isolated, washed with brine and concentrated in vacuo to approximately 100 mL. A solution of BnONH ₂ ·HCl (8.14 g, 51.0 mmol) in EtOAc (62 mL) was added and the mixture was stirred at reflux for 2 h. The reaction mixture was cooled to room temperature, washed with _H2O and brine, and the organic layer was concentrated in vacuo to give the title compound (85% purity, 19.5 g, 40.1 mmol, 83% yield) as a colorless oil; ^1H NMR (400 MHz, chloroform-d) δ 7.16 - 7.33 (m, 5H), 5.01 - 5.06 (m, 2H), 3.95 - 4.30 (m, 5H), 2.32 - 2.50 (m, 2H), 1.98 - 2.13 (m, 1H), 1.75 - 1.92 (m, 1H),1.30 - 1.40 (m, 9H), 1.12 - 1.24 (m, 3H),

ＥｔＯＡｃ（１５７ｍＬ）中のエチル（２Ｒ）－５－［（ベンジルオキシ）イミノ］－２－｛［（ｔｅｒｔ－ブトキシ）カルボニル］アミノ｝－６－クロロヘキサノエート（８５％の純度、１９．５ｇ、４０．１ｍｍｏｌ）の溶液に、ＭｓＯＨ（７．８ｍＬ、０．１２ｍｏｌ）を添加し、混合物を４２℃で２時間の間撹拌した。結果として生じた混合物をＨ_２Ｏ（１００ｍＬ）中のＫＨＣＯ_３（２０．１ｇ、０．２０１ｍｏｌ）の溶液に添加し、５２℃で２時間の間撹拌した。反応混合物を室温に冷却し、有機層を単離し、ブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（８５％の純度、１３．０ｇ、４０．０ｍｍｏｌ）定量的収量で暗オレンジ色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) δ 7.20 - 7.34 (m, 5H), 4.99 (d, J = 4.8 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.45 - 3.56 (m, 1H), 3.25 (dd, J = 14.9, 9.8 Hz, 1H), 3.08 (dt, J = 14.5, 4.3 Hz, 1H), 2.01 - 2.32 (m, 3H), 1.55 - 1.80 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H). Step 1. b: Ethyl (2R)-5-[(benzyloxy)imino]piperidine-2-carboxylate

To a solution of ethyl (2R)-5-[(benzyloxy)imino]-2-{[(tert-butoxy)carbonyl]amino}-6-chlorohexanoate (85% purity, 19.5 g, 40.1 mmol) in EtOAc (157 mL) was added MsOH (7.8 mL, 0.12 mol) and the mixture was stirred for 2 h at 42° C. The resulting mixture was added to a solution of KHCO ₃ (20.1 g, 0.201 mol) in H ₂ O (100 mL) and stirred at 52° C. for 2 h. The reaction mixture was cooled to room temperature, the organic layer was isolated, washed with _brine , dried over _Na2SO4 , and concentrated in vacuo to give the title compound (85% purity, 13.0 g, 40.0 mmol) in quantitative yield as a dark orange oil; ^1H NMR (400 MHz, chloroform-d) δ 7.20 - 7.34 (m, 5H), 4.99 (d, J = 4.8 Hz, 2H), 4.13 (q, J = 7.1 Hz, 2H), 3.45 - 3.56 (m, 1H), 3.25 (dd, J = 14.9, 9.8 Hz, 1H), 3.08 (dt, J = 14.5, 4.3 Hz, 1H), 2.01 - 2.32 (m, 3H), 1.55 - 1.80 (m, 1H), 1.21 (t, J = 7.1 Hz, 3H).

プロパン酸（２３ｍＬ、０．２４０ｍｏｌ）をＥｔＯＡｃ（９５ｍＬ）中のＮａＢＨ_４（３．０３ｇ、８０．０ｍｍｏｌ）の懸濁液に添加し、混合物を室温で１時間の間撹拌した。結果として生じた混合物を、ＥｔＯＡｃ（９５ｍＬ）およびＨ_２ＳＯ_４（１１ｍＬ、０．２０ｍｏｌ）中のエチル（２Ｒ）－５－［（ベンジルオキシ）イミノ］ピペリジン－２－カルボキシレート（８５％の純度、１３．０ｇ、４０．０ｍｍｏｌ）の溶液に－２０℃で添加し、室温で６０時間の間撹拌した。反応混合物をＨ_２Ｏ（７５ｍＬ）で希釈し、ＮＨ_４ＯＨ水溶液で中和した。有機層を単離し、ブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で約７５ｍＬの体積に濃縮した。溶液を４５℃に加温し、ＭｅＯＨ（３０ｍＬ）、続いて、ＭｅＯＨ（１５ｍＬ）中のシュウ酸（３．６０ｇ、４０．０ｍｍｏｌ）の溶液を添加した。混合物を０℃に冷却し、結果として生じた沈殿物を、真空濾過を介して単離し、ＭｅＯＨ：ＥｔＯＨ（１：４）およびＥｔＯＡｃで洗浄することで、標題化合物が（７．１７ｇ、１９．１ｍｍｏｌ、４８％の収率）得られた；¹H NMR (500 MHz, DMSO-d₆) δ 7.25 - 7.42 (m, 5H), 4.59 (s, 2H), 4.17 - 4.24 (m, 2H), 3.92 (dd, J = 12.3, 3.2 Hz, 1H), 3.34 - 3.40 (m, 1H), 3.10 (ddd, J = 15.1, 7.6, 3.9 Hz, 1H), 2.64 (t, J = 11.5 Hz, 1H), 2.13 (dt, J = 10.2, 3.4 Hz, 1H), 1.87 (dd, J = 9.0, 3.8 Hz, 1H), 1.65 (qd, J = 13.2, 3.6 Hz, 1H), 1.40 (qd, J = 12.8, 3.9 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H); M/Z: 279, [M+H]⁺, ESI⁺, RT = 0.81 (S1). Intermediate 1 (Step 1.c): Ethyl (2R,5S)-5-[(benzyloxy)amino]piperidine-2-carboxylate oxalate

Propanoic acid (23 mL, 0.240 mol) was added to a suspension of NaBH ₄ (3.03 g, 80.0 mmol) in EtOAc (95 mL) and the mixture was stirred at room temperature for 1 h. The resulting mixture was added to a solution of ethyl (2R)-5-[(benzyloxy)imino]piperidine-2-carboxylate (85% purity, 13.0 g, 40.0 mmol) in EtOAc (95 mL) and H ₂ SO ₄ (11 mL, 0.20 mol) at −20° C. and stirred at room temperature for 60 h. The reaction mixture was diluted with H ₂ O (75 mL) and neutralized with aqueous NH ₄ OH. The organic layer was isolated, washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo to a volume of about 75 mL. The solution was warmed to 45° C. and MeOH (30 mL) was added followed by a solution of oxalic acid (3.60 g, 40.0 mmol) in MeOH (15 mL). The mixture was cooled to 0° C. and the resulting precipitate was isolated via vacuum filtration and washed with MeOH:EtOH (1:4) and EtOAc to give the title compound (7.17 g, 19.1 mmol, 48% yield); ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.25 - 7.42 (m, 5H), 4.59 (s, 2H), 4.17 - 4.24 (m, 2H), 3.92 (dd, J = 12.3, 3.2 Hz, 1H), 3.34 - 3.40 (m, 1H), 3.10 (ddd, J = 15.1, 7.6, 3.9 Hz, 1H), 2.64 (t, J = 11.5 Hz, 1H), 2.13 (dt, J = 10.2, 3.4 Hz, 1H), 1.87 (dd, J = 9.0, 3.8 Hz, 1H), 1.65 (qd, J = 13.2, 3.6 Hz, 1H), 1.40 (qd, J = 12.8, 3.9 Hz, 1H), 1.23 (t, J = 7.1 Hz, 3H); M/Z: 279, [M+H] ⁺ , ESI ⁺ , RT = 0.81 (S1).

無水ＤＣＭ（３０ｍＬ）中のエチル（２Ｒ，５Ｓ）－５－［（ベンジルオキシ）アミノ］ピペリジン－２－カルボキシレートシュウ酸（２．２２ｇ、６．０３ｍｍｏｌ、中間体１）の溶液に０℃で、Ｅｔ_３Ｎ（３．６ｍＬ、２５．８ｍｍｏｌ）、ＤＭＡＰ（７６ｍｇ、０．６２２ｍｍｏｌ）およびＢｏｃ_２Ｏ（４．２ｍＬ、１８．３ｍｍｏｌ）を添加し、混合物を室温で１７時間の間撹拌した。反応混合物を飽和ＮＨ_４Ｃｌ水溶液およびＤＣＭで希釈し、有機層を単離し、Ｈ_２Ｏおよびブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～２０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（８６％の純度、１．４０ｇ、３．１８ｍｍｏｌ、５３％の収率）無色の油状物として得られた；¹H NMR (500 MHz, chloroform-d) δ 7.40 - 7.26 (m, 5H), 5.51 - 5.41 (m, 1H), 4.92 - 4.80 (m, 1H), 4.79 - 4.62 (m, 2H), 4.19 (q, J = 7.0 Hz, 3H), 3.11 (d, J = 45.4 Hz, 2H), 1.96 (s, 2H), 1.73 - 1.60 (m, 1H), 1.55 - 1.49 (m, 1H), 1.46 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H); M/Z: 379, [M+H]⁺, ESI⁺, RT = 1.09 (S2). Intermediate 2 (Step 1.d): 1-tert-butyl 2-ethyl (2R,5S)-5-[(benzyloxy)amino]piperidine-1,2-dicarboxylate

To a solution of ethyl (2R,5S)-5-[(benzyloxy)amino]piperidine-2-carboxylate oxalate (2.22 g, 6.03 mmol, intermediate 1) in anhydrous DCM (30 mL) at 0° C. was added Et ₃ N (3.6 mL, 25.8 mmol), DMAP (76 mg, 0.622 mmol) and Boc ₂ O (4.2 mL, 18.3 mmol) and the mixture was stirred at room temperature for 17 h. The reaction mixture was diluted with saturated aqueous NH ₄ Cl and DCM, the organic layer was isolated, washed with H ₂ O and brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-20% EtOAc in heptane) to give the title compound (86% purity, 1.40 g, 3.18 mmol, 53% yield) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 7.40 - 7.26 (m, 5H), 5.51 - 5.41 (m, 1H), 4.92 - 4.80 (m, 1H), 4.79 - 4.62 (m, 2H), 4.19 (q, J = 7.0 Hz, 3H), 3.11 (d, J = 45.4 Hz, 2H), 1.96 (s, 2H), 1.73 - 1.60 (m, 1H), 1.55 - 1.49 (m, 1H), 1.46 (s, 9H), 1.27 (t, J = 7.1 Hz, 3H); M/Z: 379, [M+H] ⁺ , ESI ⁺ , RT = 1.09 (S2).

Scheme for Route 2

無水ＥｔＯＨ（１Ｌ）中の１－ｔｅｒｔ－ブチル２－エチル（２Ｒ，５Ｓ）－５－［（ベンジルオキシ）アミノ］ピペリジン－１，２－ジカルボキシレート（８２％の純度、２４．９ｇ、５４．０ｍｍｏｌ、中間体２）の溶液に、１０％のＰｄ／Ｃ（２．８７ｇ、２．７０ｍｍｏｌ）を添加し、混合物を室温でＨ_２下にて２４時間の間撹拌した。反応混合物をセライトのパッドに通して濾過し、真空中で濃縮した。残留物をＥｔ_２Ｏ中に溶解させ、２ＭのＨＣｌ水溶液で洗浄した。有機層を捨て、固体ＮａＨＣＯ_３を使用して水性層を塩基性化し、次いで、ＩＰＡ：ＤＣＭ（２：８）で抽出した。有機抽出物をブラインで洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（１１．５ｇ、４２．２ｍｍｏｌ、７８％の収率）淡黄色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) 1.29 (t, J = 7.1 Hz, 3H), 1.48 (s, 9H), 1.51 - 1.70 (m, 4H), 1.93 - 2.22 (m, 2H), 3.06 - 3.38 (m, 2H), 3.66 - 3.97 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.56 - 5.01 (m, 1H). Intermediate 3 (Step 2.a): 1-tert-butyl 2-ethyl (2R,5S)-5-aminoaminopiperidine-1,2-dicarboxylate

To a solution of 1-tert-butyl 2-ethyl (2R,5S)-5-[(benzyloxy)amino]piperidine-1,2-dicarboxylate (82% purity, 24.9 g, 54.0 mmol, intermediate 2) in absolute EtOH (1 L) was added 10% Pd/C (2.87 g, 2.70 mmol) and the mixture was stirred at room temperature under H ₂ for 24 h. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo. The residue was dissolved in Et ₂ O and washed with 2M aqueous HCl. The organic layer was discarded and the aqueous layer was basified using solid NaHCO ₃ and then extracted with IPA:DCM (2:8). The organic extract was washed with brine, dried over _MgSO4 , and concentrated in vacuo to give the title compound (11.5 g, 42.2 mmol, 78% yield) as a pale yellow oil; ^1H NMR (400 MHz, chloroform-d) 1.29 (t, J = 7.1 Hz, 3H), 1.48 (s, 9H), 1.51 - 1.70 (m, 4H), 1.93 - 2.22 (m, 2H), 3.06 - 3.38 (m, 2H), 3.66 - 3.97 (m, 1H), 4.21 (q, J = 7.1 Hz, 2H), 4.56 - 5.01 (m, 1H).

ＤＣＭ（４５ｍＬ）中の１－ｔｅｒｔ－ブチル２－エチル（２Ｒ，５Ｓ）－５－アミノアミノピペリジン－１，２－ジカルボキシレート（２．５０ｇ、９．１８ｍｍｏｌ）、ＤＭＡＰ（９０ｍｇ、０．７３９ｍｍｏｌ）およびピリジン（１．４９ｍＬ、１８．４ｍｍｏｌ）の溶液に０℃で、ベンジルカルボノクロリデート（１．９９ｍＬ、１３．９ｍｍｏｌ）を添加し、反応混合物を室温で２０時間の間撹拌した。さらなる一分量のピリジン（７００μＬ、８．６ｍｍｏｌ）、ＤＭＡＰ（４２ｍｇ、０．３４ｍｍｏｌ）およびベンジルカルボノクロリデート（９３０μＬ、６．５ｍｍｏｌ）を０℃で添加し、混合物を室温で１時間の間撹拌した。反応混合物をＨ_２Ｏ（２０ｍＬ）で希釈し、ＤＣＭ（２×５０ｍＬ）で抽出した。合わせた有機抽出物を、相分離器を使用して乾燥させ、真空中で濃縮し、シリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（８４％の純度、３．１８ｇ、６．５７ｍｍｏｌ、７２％の収率）無色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) δ 7.36 - 7.21 (m, 5H), 5.16 - 4.92 (m, 3H), 4.87 - 4.50 (m, 1H), 4.13 (q, J = 6.7 Hz, 2H), 3.98 - 3.72 (m, 2H), 3.21 - 2.94 (m, 1H), 2.13 - 1.99 (m, 1H), 1.93 - 1.67 (m, 2H), 1.37 (s, 9H), 1.19 (d, J = 7.1 Hz, 3H), NH proton not observed; M/Z: 307 [M-Boc+H]⁺, ESI⁺, RT = 1.08 (S1). Step 2. b: 1-tert-butyl 2-ethyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}piperidine-1,2-dicarboxylate

To a solution of 1-tert-butyl 2-ethyl(2R,5S)-5-aminoaminopiperidine-1,2-dicarboxylate (2.50 g, 9.18 mmol), DMAP (90 mg, 0.739 mmol) and pyridine (1.49 mL, 18.4 mmol) in DCM (45 mL) at 0° C. was added benzyl carbonochloridate (1.99 mL, 13.9 mmol) and the reaction mixture was stirred at room temperature for 20 h. An additional portion of pyridine (700 μL, 8.6 mmol), DMAP (42 mg, 0.34 mmol) and benzyl carbonochloridate (930 μL, 6.5 mmol) was added at 0° C. and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with DCM (2×50 mL). The combined organic extracts were dried using a phase separator, concentrated in vacuo and purified by chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (84% purity, 3.18 g, 6.57 mmol, 72% yield) as a colorless oil; ¹ H NMR (400 MHz, chloroform-d) δ 7.36 - 7.21 (m, 5H), 5.16 - 4.92 (m, 3H), 4.87 - 4.50 (m, 1H), 4.13 (q, J = 6.7 Hz, 2H), 3.98 - 3.72 (m, 2H), 3.21 - 2.94 (m, 1H), 2.13 - 1.99 (m, 1H), 1.93 - 1.67 (m, 2H), 1.37 (s, 9H), 1.19 (d, J = 7.1 Hz, 3H), NH proton not observed; M/Z: 307 [M-Boc+H] ⁺ , ESI ⁺ , RT = 1.08 (S1).

ＥｔＯＨ（２５ｍＬ）：ＴＨＦ（２５ｍＬ）：水（２５ｍＬ）中の１－ｔｅｒｔ－ブチル２－エチル（２Ｒ，５Ｓ）－５－｛［（ベンジルオキシ）カルボニル］アミノ｝ピペリジン－１，２－ジカルボキシレート（８４％の純度、３．１８ｇ、６．５７ｍｍｏｌ）およびＬｉＯＨ・Ｈ_２Ｏ（３１１ｍｇ、７．２３ｍｍｏｌ）の混合物を、室温で２４時間の間撹拌した。反応混合物をＨ_２Ｏ（３０ｍＬ）とＥｔＯＡｃ（３０ｍＬ）との間で分配し、有機層を捨てた。水性層を次いで、１ＭのＨＣｌ水溶液を使用して酸性化し、ＥｔＯＡｃ（２×５０ｍＬ）で抽出した。合わせた有機抽出物をブライン（２０ｍＬ）で洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（８６％の純度、２．０４ｇ、４．６４ｍｍｏｌ、７１％の収率）無色の固体として得られた；Ｍ／Ｚ：３７７［Ｍ－Ｈ］^＋、ＥＳＩ^－、ＲＴ＝０．９０（Ｓ２）。 Intermediate 4 (Step 2.c): (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid

A mixture of 1-tert-butyl 2-ethyl(2R,5S)-5-{[(benzyloxy)carbonyl]amino}piperidine-1,2-dicarboxylate (84% purity, 3.18 g, 6.57 mmol) and LiOH.H ₂ O (311 mg, 7.23 mmol) in EtOH (25 mL):THF (25 mL):water (25 mL) was stirred at room temperature for 24 h. The reaction mixture was partitioned between H ₂ O (30 mL) and EtOAc (30 mL) and the organic layer was discarded. The aqueous layer was then acidified using 1 M aqueous HCl and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO ₄ and concentrated in vacuo to give the title compound (86% purity, 2.04 g, 4.64 mmol, 71% yield) as a colorless solid; M/Z: 377 [M−H] ⁺ , ESI ⁻ , RT=0.90 (S2).

Scheme for Route 3

ＭｅＯＨ（１００ｍＬ）中のエチル（２Ｓ，５Ｒ）－５－［（ベンジルオキシ）アミノ］ピペリジン－２－カルボキシレート；シュウ酸（１０ｇ、２７．１ｍｍｏｌ）の溶液に、ＳＣＸ粉末（５０ｇ）を添加し、混合物を室温で１０分間撹拌した。反応混合物を真空下で濾過し、ＭｅＯＨ中４ＭのＮＨ_３で洗浄し、真空中で濃縮することで、標題化合物が（６．２２ｇ、２２．３ｍｍｏｌ、８２％の収率）粘稠な黄色の油状物として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 7.40 - 7.21 (m, 5H), 6.46 (s, 1H), 4.57 (s, 2H), 4.07 (q, J = 7.1 Hz, 2H), 3.19 - 3.08 (m, 3H), 2.84 - 2.70 (m, 1H), 2.23 (dd, J = 11.7, 9.9 Hz, 1H), 1.92 - 1.75 (m, 2H), 1.44 - 1.25 (m, 1H), 1.23 - 1.08 (m, 4H); M/Z: 279 [M+H]⁺, ESI⁺, RT = 0.50 (S2). Step 3. a: Ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate

To a solution of ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate; oxalic acid (10 g, 27.1 mmol) in MeOH (100 mL) was added SCX powder (50 g) and the mixture was stirred at room temperature for 10 minutes. The reaction mixture was filtered under vacuum, washed with 4M _NH3 in MeOH, and concentrated in vacuo to give the title compound (6.22 g, 22.3 mmol, 82% yield) as a viscous yellow oil; ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.40 - 7.21 (m, 5H), 6.46 (s, 1H), 4.57 (s, 2H), 4.07 (q, J = 7.1 Hz, 2H), 3.19 - 3.08 (m, 3H), 2.84 - 2.70 (m, 1H), 2.23 (dd, J = 11.7, 9.9 Hz, 1H), 1.92 - 1.75 (m, 2H), 1.44 - 1.25 (m, 1H), 1.23 - 1.08 (m, 4H); M/Z: 279 [M+H] ⁺ , ESI ⁺ , RT = 0.50 (S2).

Ｂｏｃ_２Ｏ（７．３２ｇ、３３．５ｍｍｏｌ）を、無水ＤＣＭ（１１０ｍＬ）中のエチル（２Ｓ，５Ｒ）－５－［（ベンジルオキシ）アミノ］ピペリジン－２－カルボキシレート（６．２２ｇ、２２．３ｍｍｏｌ）およびＥｔ_３Ｎ（１２ｍＬ、８９．４ｍｍｏｌ）の溶液に添加し、混合物を室温で２．５時間の間撹拌した。反応混合物を飽和ＮＨ_４Ｃｌ水溶液（１００ｍＬ）およびブライン（１００ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。結果として生じた残留物をシリカゲル（ヘプタン中５～５０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（９４％の純度、６．８２ｇ、１６．９ｍｍｏｌ、７６％の収率）無色の油状物として得られた；¹H NMR (500 MHz, chloroform-d) δ 7.44 - 7.27 (m, 5H), 5.48 (s, 1H), 4.87 (d, J = 9.9 Hz, 1H), 4.79 - 4.58 (m, 2H), 4.20 (q, J = 7.0 Hz, 3H), 3.12 (d, J = 44.6 Hz, 2H), 1.97 (s, 2H), 1.77 - 1.62 (m, 2H), 1.58 - 1.50 (m, 1H), 1.46 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H); M/Z: 324 [M-^tButyl+H]⁺, ESI⁺, RT = 1.34 (S1). Intermediate 5 (Step 3.b): 1-tert-butyl 2-ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-1,2-dicarboxylate

Boc ₂ O (7.32 g, 33.5 mmol) was added to a solution of ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-2-carboxylate (6.22 g, 22.3 mmol) and Et ₃ N (12 mL, 89.4 mmol) in anhydrous DCM (110 mL) and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was washed with saturated aqueous NH ₄ Cl (100 mL) and brine (100 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel (5-50% EtOAc in heptane) to give the title compound (94% purity, 6.82 g, 16.9 mmol, 76% yield) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 7.44 - 7.27 (m, 5H), 5.48 (s, 1H), 4.87 (d, J = 9.9 Hz, 1H), 4.79 - 4.58 (m, 2H), 4.20 (q, J = 7.0 Hz, 3H), 3.12 (d, J = 44.6 Hz, 2H), 1.97 (s, 2H), 1.77 - 1.62 (m, 2H), 1.58 - 1.50 (m, 1H), 1.46 (s, 9H), 1.28 (t, J = 7.1 Hz, 3H); M/Z: 324 [M- ^t Butyl+H] ⁺ , ESI ⁺ , RT = 1.34 (S1).

Scheme for Route 4

無水ＤＭＦ（２４ｍＬ）中の（２Ｒ，５Ｓ）－５－｛［（ベンジルオキシ）カルボニル］アミノ｝－１－［（ｔｅｒｔ－ブトキシ）カルボニル］ピペリジン－２－カルボン酸（９０％の純度、２．０４ｇ、４．８５ｍｍｏｌ、中間体４）、４－（トリフルオロメチル）ベンゾヒドラジド（１．２９ｇ、６．３１ｍｍｏｌ）およびＨＡＴＵ（２．２１ｇ、５．８２ｍｍｏｌ）の溶液に、ＤＩＰＥＡ（１．７ｍＬ、９．７０ｍｍｏｌ）を添加し、混合物を室温で１６時間の間撹拌した。反応混合物をＥｔＯＡｃ（１００ｍＬ）と１ＭのＨＣｌ水溶液（５０ｍＬ）との間で分配した。有機層を単離し、ブライン（５×５０ｍＬ）で洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（７０％の純度、３．８０ｇ、４．７１ｍｍｏｌ、９７％の収率）オフホワイトの固体として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 10.59 (s, 1H), 10.01 (s, 1H), 8.07 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.46 - 7.27 (m, 6H), 5.05 (s, 2H), 4.84 - 4.52 (m, 2H), 4.12 - 3.92 (m, 1H), 3.74 - 3.46 (m, 2H), 2.23 - 2.03 (m, 1H), 1.78 - 1.62 (m, 1H), 1.63 - 1.49 (m, 1H), 1.38 (s, 9H); M/Z: 465 [M-Boc+H]⁺, ESI⁺, RT = 1.01 (S2). Step 4. a: tert-Butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-({[4-(trifluoromethyl)phenyl]formohydrazide}carbonyl)piperidine-1-carboxylate

To a solution of (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid (90% purity, 2.04 g, 4.85 mmol, intermediate 4), 4-(trifluoromethyl)benzohydrazide (1.29 g, 6.31 mmol) and HATU (2.21 g, 5.82 mmol) in anhydrous DMF (24 mL) was added DIPEA (1.7 mL, 9.70 mmol) and the mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc (100 mL) and 1 M aqueous HCl (50 mL). The organic layer was isolated, washed with brine (5×50 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (70% purity, 3.80 g, 4.71 mmol, 97% yield) as an off-white solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 10.01 (s, 1H), 8.07 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 8.3 Hz, 2H), 7.46 - 7.27 (m, 6H), 5.05 (s, 2H), 4.84 - 4.52 (m, 2H), 4.12 - 3.92 (m, 1H), 3.74 - 3.46 (m, 2H), 2.23 - 2.03 (m, 1H), 1.78 - 1.62 (m, 1H), 1.63 - 1.49 (m, 1H), 1.38 (s, 9H); M/Z: 465 [M-Boc+H] ⁺ , ESI ⁺ , RT = 1.01 (S2).

ＡＣＮ（１００ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－｛［（ベンジルオキシ）カルボニル］アミノ｝－２－（｛［４－（トリフルオロメチル）フェニル］ホルモヒドラジド｝カルボニル）ピペリジン－１－カルボキシレート（７０％の純度、３．８０ｇ、４．７１ｍｍｏｌ）、ＴｓＣｌ（２．７０ｇ、１４．１ｍｍｏｌ）およびＫ_２ＣＯ_３（１．９５ｇ、１４．１ｍｍｏｌ）の懸濁液を、８０℃で３時間の間撹拌した。反応混合物をＥｔＯＡｃ（１００ｍＬ）とＨ_２Ｏ（１００ｍＬ）との間で分配した。有機層を単離し、ブライン（５０ｍＬ）で洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製した。結果として生じた残留物をＥｔ_２Ｏで粉砕し、固体を捨て、濾液を真空中で濃縮し、分取ＨＰＬＣ（方法５）によって精製することで、標題化合物が（７５％の純度、２．９０ｇ、３．９８ｍｍｏｌ、８４％の収率）淡黄色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) δ 8.08 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.34 - 7.21 (m, 5H), 5.78 - 5.41 (m, 1H), 5.17 - 4.95 (m, 3H), 4.73 (s, 1H), 3.86 (s, 1H), 3.11 (s, 1H), 2.24 - 2.02 (m, 2H), 1.84 (d, J = 22.6 Hz, 2H), 1.41 (s, 9H); M/Z: 447 [M-Boc+H]⁺, ESI⁺, RT = 1.22 (S2). Step 4. b: tert-Butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

A suspension of tert-butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-({[4-(trifluoromethyl)phenyl]formohydrazide}carbonyl)piperidine-1-carboxylate (70% purity, 3.80 g, 4.71 mmol), TsCl (2.70 g, 14.1 mmol) and K ₂ CO ₃ (1.95 g, 14.1 mmol) in ACN (100 mL) was stirred at 80° C. for 3 h. The reaction mixture was partitioned between EtOAc (100 mL) and H ₂ O (100 mL). The organic layer was isolated, washed with brine (50 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane). The resulting residue was triturated with Et ₂ O, the solids were discarded, and the filtrate was concentrated in vacuo and purified by preparative HPLC (Method 5) to give the title compound (75% purity, 2.90 g, 3.98 mmol, 84% yield) as a pale yellow oil; ¹ H NMR (400 MHz, chloroform-d) δ 8.08 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.34 - 7.21 (m, 5H), 5.78 - 5.41 (m, 1H), 5.17 - 4.95 (m, 3H), 4.73 (s, 1H), 3.86 (s, 1H), 3.11 (s, 1H), 2.24 - 2.02 (m, 2H), 1.84 (d, J = 22.6 Hz, 2H), 1.41 (s, 9H); M/Z: 447 [M-Boc+H] ⁺ , ESI ⁺ , RT = 1.22 (S2).

無水ＥｔＯＨ（８０ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－｛［（ベンジルオキシ）カルボニル］アミノ｝－２－｛５－［４－（トリフルオロメチル）フェニル］－１，３，４－オキサジアゾール－２－イル｝ピペリジン－１－カルボキシレート（７５％の純度、２．９０ｇ、３．９８ｍｍｏｌ）の溶液に、Ｐｄ／Ｃ（１０％、０．２１ｇ、０．１９９ｍｍｏｌ）を添加し、混合物をＨ_２下にて室温で２４時間の間撹拌した。反応混合物をセライトのパッドに通して濾過し、濾液を真空中で濃縮した。残留物をＥｔＯＡｃと２ＭのＨＣｌ水溶液との間で分配した。有機層を単離し、２０分後に沈殿が観察された。懸濁液を真空下で濾過して、Ｈ_２Ｏで洗浄し、標題化合物がＨＣｌ塩として（０．７６ｇ、１．６８ｍｍｏｌ、４２％の収率）白色の固体として得られた；¹H NMR (400 MHz, chloroform-d) δ 8.74 (s, 3H), 8.08 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 5.67 (s, 1H), 4.51 - 4.36 (m, 1H), 3.63 (s, 1H), 3.19 (s, 2H), 2.61 - 2.47 (m, 1H), 2.31 - 2.14 (m, 2H), 1.47 (s, 9H); M/Z: 413 [M+H]⁺, ESI⁺, RT = 1.08 (S2). Intermediate 6 (Step 4.c): tert-Butyl (2R,5S)-5-amino-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

To a solution of tert-butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (75% purity, 2.90 g, 3.98 mmol) in absolute EtOH (80 mL) was added Pd/C (10%, 0.21 g, 0.199 mmol) and the mixture was stirred under _H2 at room temperature for 24 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was partitioned between EtOAc and 2M aqueous HCl. The organic layer was isolated and precipitation was observed after 20 min. The suspension was filtered under vacuum and washed with _H2O to give the title compound as the HCl salt (0.76 g, 1.68 mmol, 42% yield) as a white solid; ^1H NMR (400 MHz, chloroform-d) δ 8.74 (s, 3H), 8.08 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.3 Hz, 2H), 5.67 (s, 1H), 4.51 - 4.36 (m, 1H), 3.63 (s, 1H), 3.19 (s, 2H), 2.61 - 2.47 (m, 1H), 2.31 - 2.14 (m, 2H), 1.47 (s, 9H); M/Z: 413 [M+H] ⁺ , ESI ⁺ , RT = 1.08 (S2).

Scheme for Route 5

無水ＤＭＦ（５ｍＬ）中の３－クロロ－４－（トリフルオロメチル）フェノール（１．００ｇ、５．０９ｍｍｏｌ）、ｔｅｒｔ－ブチル２－ブロモアセテート（０．８３ｍＬ、５．６０ｍｍｏｌ）およびＫ_２ＣＯ_３（１．４１ｇ、１０．２ｍｍｏｌ）の混合物を６５℃で２．５時間の間撹拌した。反応混合物を室温に冷却し、Ｈ_２Ｏ（３０ｍＬ）で希釈し、ＥｔＯＡｃ（２×３０ｍＬ）で抽出した。合わせた有機抽出物をブライン（４０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中５～５０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（１．３５ｇ、４．３５ｍｍｏｌ、８５％の収率）無色の油状物として得られた；¹H NMR (500 MHz, chloroform-d) δ 7.61 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 6.88 - 6.79 (m, 1H), 4.56 (s, 2H), 1.50 (s, 9H); M/Z: not observed, ESI⁺, RT = 1.16 (S2). Step 5. a: tert-Butyl 2-[3-chloro-4-(trifluoromethyl)phenoxy]acetate

A mixture of 3-chloro-4-(trifluoromethyl)phenol (1.00 g, 5.09 mmol), tert-butyl 2-bromoacetate (0.83 mL, 5.60 mmol) and K ₂ CO ₃ (1.41 g, 10.2 mmol) in anhydrous DMF (5 mL) was stirred at 65° C. for 2.5 h. The reaction mixture was cooled to room temperature, diluted with H ₂ O (30 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (40 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (5-50% EtOAc in heptane) to give the title compound (1.35 g, 4.35 mmol, 85% yield) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 7.61 (d, J = 8.8 Hz, 1H), 7.02 (d, J = 2.5 Hz, 1H), 6.88 - 6.79 (m, 1H), 4.56 (s, 2H), 1.50 (s, 9H); M/Z: not observed, ESI ⁺ , RT = 1.16 (S2).

１，４－ジオキサン（１０ｍＬ）中４ＭのＨＣｌ中のｔｅｒｔ－ブチル２－［３－クロロ－４－（トリフルオロメチル）フェノキシ］アセテート（１．３５ｇ、４．３５ｍｍｏｌ）の溶液を、５０℃で６時間の間撹拌した。反応混合物を真空中で濃縮することで、標題化合物が（１．０９ｇ、４．２８ｍｍｏｌ、９９％の収率）白色の固体として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 13.19 (s, 1H), 7.76 (d, J = 8.9 Hz, 1H), 7.31 (d, J = 2.5 Hz, 1H), 7.07 (dd, J = 8.7, 2.4 Hz, 1H), 4.86 (s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ -59.84 (2F, s). Intermediate 7 (Step 5.b): 2-[3-chloro-4-(trifluoromethyl)phenoxy]acetic acid

A solution of tert-butyl 2-[3-chloro-4-(trifluoromethyl)phenoxy]acetate (1.35 g, 4.35 mmol) in 4 M HCl in 1,4-dioxane (10 mL) was stirred at 50° C. for 6 h. The reaction mixture was concentrated in vacuo to give the title compound (1.09 g, 4.28 mmol, 99% yield) as a white solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 13.19 (s, 1H), 7.76 (d, J = 8.9 Hz, 1H), 7.31 (d, J = 2.5 Hz, 1H), 7.07 (dd, J = 8.7, 2.4 Hz, 1H), 4.86 (s, 2H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -59.84 (2F, s).

Following general route 5, the intermediates in Table 1 were synthesized using the corresponding starting materials as exemplified by intermediate 7.

Scheme for Route 6

ＤＭＦ（６ｍＬ）中のｔｅｒｔ－ブチル２－ブロモアセテート（１．１ｍＬ、７．１６ｍｍｏｌ）、２－クロロ－５－ヒドロキシベンゾニトリル（１．００ｇ、６．５１ｍｍｏｌ）およびＫ_２ＣＯ_３（１．８０ｇ、１３．０ｍｍｏｌ）の混合物を、６５℃で２時間の間撹拌した。反応混合物をＨ_２Ｏ（３０ｍＬ）で希釈し、ＥｔＯＡｃ（２×５０ｍＬ）で抽出した。合わせた有機抽出物をブライン（３０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（８４％の純度、２．１０ｇ、６．５９ｍｍｏｌ）定量的収量でオレンジ色の油状物として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 7.65 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7.32 (dd, J = 9.0, 3.1 Hz, 1H), 4.79 (s, 2H), 1.43 (s, 9H); M/Z: 269, 271 [M+H]⁺, ESI⁺, RT = 1.11 (S2). Step 6. a: tert-Butyl 2-(4-chloro-3-cyanophenoxy)acetate

A mixture of tert-butyl 2-bromoacetate (1.1 mL, 7.16 mmol), 2-chloro-5-hydroxybenzonitrile (1.00 g, 6.51 mmol) and K ₂ CO ₃ (1.80 g, 13.0 mmol) in DMF (6 mL) was stirred for 2 h at 65° C. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (30 mL), dried over _Na2SO4 , and concentrated in _vacuo to give the title compound (84% purity, 2.10 g, 6.59 mmol) in quantitative yield as an orange oil; ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.65 (d, J = 9.0 Hz, 1H), 7.61 (d, J = 3.1 Hz, 1H), 7.32 (dd, J = 9.0, 3.1 Hz, 1H), 4.79 (s, 2H), 1.43 (s, 9H); M/Z: 269, 271 [M+H] ⁺ , ESI ⁺ , RT = 1.11 (S2).

ＤＣＭ（５ｍＬ）中のｔｅｒｔ－ブチル２－（４－クロロ－３－シアノ－フェノキシ）アセテート（８４％の純度、２．５０ｇ、７．８４ｍｍｏｌ）の溶液に、ＴＦＡ（３．０ｍＬ、３９．２ｍｍｏｌ）を添加し、混合物を５０℃で２．５時間の間撹拌した。反応混合物を真空中で濃縮し、残留物をＨ_２Ｏ中に懸濁させ、室温で１５分間撹拌した。結果として生じた沈殿物を真空下で濾過して、Ｈ_２Ｏで洗浄し、標題化合物が（９４％の純度、１．０３ｇ、４．５８ｍｍｏｌ、５８％の収率）オフホワイトの固体として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 7.69 - 7.56 (m, 2H), 7.32 (dd, J = 9.0, 3.1 Hz, 1H), 4.81 (s, 2H); M/Z: 210, 212 [M-H]^-, ESI^-, RT = 0.76 (S2). Intermediate 16 (Step 6.b): 2-(4-chloro-3-cyanophenoxy)acetic acid

To a solution of tert-butyl 2-(4-chloro-3-cyano-phenoxy)acetate (84% purity, 2.50 g, 7.84 mmol) in DCM (5 mL) was added TFA (3.0 mL, 39.2 mmol) and the mixture was stirred for 2.5 h at 50° C. The reaction mixture was concentrated in vacuo and the residue was suspended in H ₂ O and stirred at rt for 15 min. The resulting precipitate was filtered under vacuum and washed with _H2O to give the title compound (94% purity, 1.03 g, 4.58 mmol, 58% yield) as an off-white solid; ^1H NMR (400 MHz, DMSO- _d6 ) δ 13.13 (s, 1H), 7.69 - 7.56 (m, 2H), 7.32 (dd, J = 9.0, 3.1 Hz, 1H), 4.81 (s, 2H); M/Z: 210, 212 [MH] ^- , ^ESI- , RT = 0.76 (S2).

Scheme for Route 7

無水ＤＭＦ（１０ｍＬ）中の２－クロロ－５－ヒドロキシベンズアルデヒド（１．０ｇ、６．３９ｍｍｏｌ）の溶液に、Ｋ_２ＣＯ_３（１．７７ｇ、１２．８ｍｍｏｌ）、続いてｔｅｒｔ－ブチルブロモアセテート（１．０ｍＬ、７．０３ｍｍｏｌ）を添加し、混合物を６５℃で１時間の間撹拌した。反応混合物を室温に冷却し、Ｈ_２Ｏ（１００ｍＬ）上に注ぎ、ＥｔＯＡｃ（２×７０ｍＬ）で抽出した。合わせた有機抽出物をブライン（１００ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中１０～８０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（１．７０ｍｇ、６．２３ｍｍｏｌ、９８％の収率）白色の固体として得られた；¹H NMR (500 MHz, CDCl₃) δ 10.42 (s, 1H), 7.40 - 7.30 (m, 2H), 7.15 (dd, J = 8.8, 3.2 Hz, 1H), 4.55 (s, 2H), 1.49 (s, 9H); M/Z: no mass ion observed [M+H]⁺, ESI⁺, RT = 1.01 (S2). Step 7. a: tert-Butyl 2-(4-chloro-3-formylphenoxy)acetate

To a solution of 2-chloro-5-hydroxybenzaldehyde (1.0 g, 6.39 mmol) in anhydrous DMF (10 mL) was added K ₂ CO ₃ (1.77 g, 12.8 mmol) followed by tert-butyl bromoacetate (1.0 mL, 7.03 mmol) and the mixture was stirred at 65° C. for 1 h. The reaction mixture was cooled to room temperature, poured onto H ₂ O (100 mL) and extracted with EtOAc (2×70 mL). The combined organic extracts were washed with brine (100 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (10-80% EtOAc in heptane) to give the title compound (1.70 mg, 6.23 mmol, 98% yield) as a white solid; ¹ H NMR (500 MHz, CDCl ₃ ) δ 10.42 (s, 1H), 7.40 - 7.30 (m, 2H), 7.15 (dd, J = 8.8, 3.2 Hz, 1H), 4.55 (s, 2H), 1.49 (s, 9H); M/Z: no mass ion observed [M+H] ⁺ , ESI ⁺ , RT = 1.01 (S2).

無水ＤＣＭ（１０ｍＬ）中のｔｅｒｔ－ブチル２－（４－クロロ－３－ホルミルフェノキシ）アセテート（１．０ｇ、３．６６ｍｍｏｌ）の溶液に０℃で、ＤＡＳＴ（０．７２ｍＬ、５．４９ｍｍｏｌ）を滴下により添加し、混合物を室温で２０時間の間撹拌した。反応混合物を飽和ＮａＨＣＯ_３水溶液（３０ｍＬ）上に注ぎ、ＤＣＭ（２×３０ｍＬ）で抽出した。合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮し、シリカゲル（ヘプタン中１０～４０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（８０９ｍｇ、２．７４ｍｍｏｌ、７５％の収率）無色の油状物として得られた；¹H NMR (500 MHz, chloroform-d) δ 7.32 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 3.0 Hz, 1H), 7.02 - 6.76 (m, 2H), 4.53 (s, 2H), 1.49 (s, 9H); ¹⁹F NMR (376 MHz, chloroform-d) δ -115.44; M/Z: 316, 318 [M+Na]⁺, ESI⁺, RT = 1.08 (S2). Step 7. b: tert-Butyl 2-[4-chloro-3-(difluoromethyl)phenoxy]acetate

To a solution of tert-butyl 2-(4-chloro-3-formylphenoxy)acetate (1.0 g, 3.66 mmol) in anhydrous DCM (10 mL) at 0° C., DAST (0.72 mL, 5.49 mmol) was added dropwise and the mixture was stirred at room temperature for 20 h. The reaction mixture was poured onto saturated aqueous NaHCO ₃ solution (30 mL) and extracted with DCM (2×30 mL). The combined organic extracts were dried over Na ₂ SO ₄ , concentrated in vacuo, and purified by chromatography on silica gel (10-40% EtOAc in heptane) to give the title compound (809 mg, 2.74 mmol, 75% yield) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 7.32 (d, J = 8.8 Hz, 1H), 7.14 (d, J = 3.0 Hz, 1H), 7.02 - 6.76 (m, 2H), 4.53 (s, 2H), 1.49 (s, 9H); ¹⁹ F NMR (376 MHz, chloroform-d) δ -115.44; M/Z: 316, 318 [M+Na] ⁺ , ESI ⁺ , RT = 1.08 (S2).

１，４－ジオキサン（１０ｍＬ）中のｔｅｒｔ－ブチル２－［４－クロロ－３－（ジフルオロメチル）フェノキシ］アセテート（８０９ｍｇ、２．７４ｍｍｏｌ）の溶液に０℃で、１，４－ジオキサン（３．４ｍＬ、１３．７ｍｍｏｌ）中４ＭのＨＣｌを添加し、混合物をＮ_２下にて室温で２０時間の間撹拌した。１，４－ジオキサン（３．４ｍＬ、１３．７ｍｍｏｌ）中４ＭのＨＣｌのさらなる一分量を添加し、混合物を５０℃で７時間の間撹拌した。１，４－ジオキサン（３．４ｍＬ、１３．７ｍｍｏｌ）中４ＭのＨＣｌのさらなる一分量を添加し、混合物を室温で２０時間の間撹拌した。反応混合物を真空中で濃縮し、Ｈ_２Ｏを使用して粉砕し、真空濾過下で１時間の間乾燥させることで、標題化合物が（５７４ｍｇ、２．３５ｍｍｏｌ、８６％の収率）白色の粉末として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (d, J = 8.8 Hz, 1H), 7.30 - 6.97 (m, 3H), 4.78 (s, 2H); M/Z: 235, 237 [M-H]^-, ESI^-, RT = 1.07 (S2). Intermediate 17 (Step 7.c): 2-[4-chloro-3-(difluoromethyl)phenoxy]acetic acid

To a solution of tert-butyl 2-[4-chloro-3-(difluoromethyl)phenoxy]acetate (809 mg, 2.74 mmol) in 1,4-dioxane (10 mL) at 0° C. was added 4 M HCl in 1,4-dioxane (3.4 mL, 13.7 mmol) and the mixture was stirred at room temperature under N ₂ for 20 h. An additional portion of 4 M HCl in 1,4-dioxane (3.4 mL, 13.7 mmol) was added and the mixture was stirred at 50° C. for 7 h. An additional portion of 4 M HCl in 1,4-dioxane (3.4 mL, 13.7 mmol) was added and the mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo, triturated with H ₂ O, and dried under vacuum filtration for 1 h to give the title compound (574 mg, 2.35 mmol, 86% yield) as a white powder; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.50 (d, J = 8.8 Hz, 1H), 7.30 - 6.97 (m, 3H), 4.78 (s, 2H); M/Z: 235, 237 [MH] ^- , ESI ^- , RT = 1.07 (S2).

The intermediates in Table 2 were synthesized according to general route 7 using the corresponding starting materials as exemplified by intermediate 17.

Scheme for Route 8

無水ＡＣＮ（５０ｍＬ）中の４－（トリフルオロメチル）フェノール（２．００ｇ、１２．３ｍｍｏｌ）およびエチル２－ブロモアセテート（１．４ｍＬ、１２．６ｍｍｏｌ）の懸濁液に、Ｃｓ_２ＣＯ_３（６．００ｇ、１８．４ｍｍｏｌ）を添加し、混合物を室温で１７時間の間撹拌した。反応混合物をＥｔＯＡｃ（２０ｍＬ）で希釈し、Ｈ_２Ｏ（２×２０ｍＬ）およびブライン（２０ｍＬ）で洗浄し、相分離器を使用して乾燥させ、真空中で濃縮した。残留物をＴＨＦ（５０ｍＬ）中に溶解させ、０．５ＭのＬｉＯＨ水溶液（４９ｍＬ、２４．７ｍｍｏｌ）の溶液を添加し、混合物を室温で１．５時間の間撹拌した。反応混合物をＨ_２Ｏ（２０ｍＬ）で希釈し、ＥｔＯＡｃ（２×２０ｍＬ）で抽出し、有機抽出物を捨てた。水溶液を次いで、１ＭのＨＣｌ水溶液を使用してｐＨ１～２に酸性化し、ＤＣＭ（３×２０ｍＬ）で抽出した。合わせた有機抽出物を、相分離器を使用して乾燥させ、真空中で濃縮することで、標題化合物が（２．９０ｇ、１２．９ｍｍｏｌ）定量的収量で白色の固体として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 13.16 (s, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 4.79 (s, 2H); M/Z: 219 [M-H]^-, ESI-, RT = 1.03 (S1). Intermediate 18: 2-[4-(trifluoromethyl)phenoxy]acetic acid

To a suspension of 4-(trifluoromethyl)phenol (2.00 g, 12.3 mmol) and ethyl 2-bromoacetate (1.4 mL, 12.6 mmol) in anhydrous ACN (50 mL) was added Cs ₂ CO ₃ (6.00 g, 18.4 mmol) and the mixture was stirred at room temperature for 17 h. The reaction mixture was diluted with EtOAc (20 mL), washed with H ₂ O (2×20 mL) and brine (20 mL), dried using a phase separator and concentrated in vacuo. The residue was dissolved in THF (50 mL) and a solution of 0.5 M aqueous LiOH (49 mL, 24.7 mmol) was added and the mixture was stirred at room temperature for 1.5 h. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (2×20 mL) and the organic extracts were discarded. The aqueous solution was then acidified to pH 1-2 using 1M aqueous HCl and extracted with DCM (3 x 20 mL). The combined organic extracts were dried using a phase separator and concentrated in vacuo to give the title compound (2.90 g, 12.9 mmol) in quantitative yield as a white solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 13.16 (s, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.10 (d, J = 8.6 Hz, 2H), 4.79 (s, 2H); M/Z: 219 [MH] ^- , ESI-, RT = 1.03 (S1).

Scheme for Route 9

ＤＣＭ（４５ｍＬ）中の２－（４－クロロ－３－フルオロフェノキシ）酢酸（５．１６ｇ、２２．７ｍｍｏｌ）の溶液に０℃で、シュウ酸ジクロリド（１０ｍＬ、０．１１５ｍｏｌ）、続いてＤＭＦ（８１μＬ、１．１１ｍｍｏｌ）を添加し、混合物を室温で１７時間の間撹拌した。反応混合物を真空中で濃縮することで、標題化合物が（９０％の純度、５．３０ｇ、２１．４ｍｍｏｌ、９４％の収率）オレンジ色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) δ 7.31 (t, J = 8.6 Hz, 1H), 6.75 (dt, J = 10.2, 2.9 Hz, 1H), 6.66 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4.96 (s, 2H). Intermediate 19: 2-(4-chloro-3-fluorophenoxy)acetyl chloride

To a solution of 2-(4-chloro-3-fluorophenoxy)acetic acid (5.16 g, 22.7 mmol) in DCM (45 mL) at 0° C. was added oxalyl dichloride (10 mL, 0.115 mol) followed by DMF (81 μL, 1.11 mmol) and the mixture was stirred at room temperature for 17 h. The reaction mixture was concentrated in vacuo to give the title compound (90% purity, 5.30 g, 21.4 mmol, 94% yield) as an orange oil; ¹ H NMR (400 MHz, chloroform-d) δ 7.31 (t, J = 8.6 Hz, 1H), 6.75 (dt, J = 10.2, 2.9 Hz, 1H), 6.66 (ddd, J = 8.9, 2.9, 1.2 Hz, 1H), 4.96 (s, 2H).

Following general route 9, the intermediates in Table 3 were synthesized using the corresponding starting materials as exemplified by intermediate 19.

Scheme for Route 10

無水ＥｔＯＨ（２００ｍＬ）中の１－ｔｅｒｔ－ブチル２－エチル（２Ｒ，５Ｓ）－５－［（ベンジルオキシ）アミノ］ピペリジン－１，２－ジカルボキシレート（９３％の純度、８．７ｇ、２１．３ｍｍｏｌ、中間体２）の溶液にＮ_２下にて、Ｐｄ／Ｃ（１０％、２．２８ｇ、２．１４ｍｍｏｌ）を添加し、混合物をＨ_２下にて室温で１７時間の間撹拌した。反応混合物をセライトのパッドに通して濾過し、濾液を真空中で濃縮した。第１にＭｅＯＨでフラッシュするとともに第２にＭｅＯＨ中３ＭのＮＨ_３で溶出するＳＣＸ－２カートリッジを使用して、残留物を精製することで、標題化合物が（４．８８ｇ、１７．０ｍｍｏｌ、８０％の収率）淡黄色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) δ 4.98 - 4.57 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.87 - 3.64 (m, 1H), 3.35 - 2.99 (m, 2H), 2.14 - 1.92 (m, 2H), 1.64 - 1.52 (m, 2H), 1.45 (s, 11H), 1.26 (t, J = 7.1 Hz, 3H). Intermediate 3 (Step 10.a): 1-tert-butyl 2-ethyl (2R,5S)-5-aminoaminopiperidine-1,2-dicarboxylate

To a solution of 1-tert-butyl 2-ethyl (2R,5S)-5-[(benzyloxy)amino]piperidine-1,2-dicarboxylate (93% purity, 8.7 g, 21.3 mmol, intermediate 2) in absolute EtOH (200 mL) under _N was added Pd/C (10%, 2.28 g, 2.14 mmol) and the mixture was stirred at room temperature under _H for 17 h. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated in vacuo. The residue was purified using an SCX-2 cartridge, first flushed with MeOH and secondly eluted with 3M _NH3 in MeOH, to give the title compound (4.88 g, 17.0 mmol, 80% yield) as a pale yellow oil; ¹ H NMR (400 MHz, chloroform-d) δ 4.98 - 4.57 (m, 1H), 4.18 (q, J = 7.1 Hz, 2H), 3.87 - 3.64 (m, 1H), 3.35 - 2.99 (m, 2H), 2.14 - 1.92 (m, 2H), 1.64 - 1.52 (m, 2H), 1.45 (s, 11H), 1.26 (t, J = 7.1 Hz, 3H).

ＤＣＭ（１７０ｍＬ）中の１－ｔｅｒｔ－ブチル２－エチル（２Ｒ，５Ｓ）－５－アミノアミノピペリジン－１，２－ジカルボキシレート（４．８９ｇ、１７．１ｍｍｏｌ）およびＥｔ_３Ｎ（１４ｍＬ、０．１０３ｍｏｌ）の混合物に０℃で、ＤＣＭ（１０ｍＬ）中の２－（４－クロロ－３－フルオロ－フェノキシ）アセチルクロリド（４．１９ｇ、１８．８ｍｍｏｌ、中間体１９）の溶液を滴下により添加し、室温で４８時間の間撹拌した。反応混合物をＤＣＭ（２５０ｍＬ）で希釈し、飽和ＮａＨＣＯ_３水溶液（２×１００ｍＬ）およびブライン（１００ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～５０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（７．１４ｇ、１５．６ｍｍｏｌ、９１％の収率）無色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) δ 7.32 (t, J = 8.6 Hz, 1H), 6.86 - 6.72 (m, 2H), 6.69 - 6.63 (m, 1H), 4.98 - 4.66 (m, 1H), 4.45 (s, 2H), 4.29 - 4.13 (m, 3H), 4.09 - 3.87 (m, 1H), 3.33 - 3.10 (m, 1H), 2.23 - 2.02 (m, 1H), 2.00 - 1.71 (m, 2H), 1.56 (s, 1H), 1.44 (s, 9H), 1.28 (t, J = 7.2 Hz, 3H); M/Z: 459, 461 [M+H]⁺, ESI⁺, RT = 3.83 (S4). Step 10. b: 1-tert-butyl 2-ethyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1,2-dicarboxylate

To a mixture of 1-tert-butyl 2-ethyl(2R,5S)-5-aminoaminopiperidine-1,2-dicarboxylate (4.89 g, 17.1 mmol) and Et ₃ N (14 mL, 0.103 mol) in DCM (170 mL) was added dropwise a solution of 2-(4-chloro-3-fluoro-phenoxy)acetyl chloride (4.19 g, 18.8 mmol, intermediate 19) in DCM (10 mL) at 0° C. and stirred at room temperature for 48 h. The reaction mixture was diluted with DCM (250 mL), washed with saturated aqueous NaHCO ₃ (2×100 mL) and brine (100 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-50% EtOAc in heptane) to give the title compound (7.14 g, 15.6 mmol, 91% yield) as a colorless oil; ¹ H NMR (400 MHz, chloroform-d) δ 7.32 (t, J = 8.6 Hz, 1H), 6.86 - 6.72 (m, 2H), 6.69 - 6.63 (m, 1H), 4.98 - 4.66 (m, 1H), 4.45 (s, 2H), 4.29 - 4.13 (m, 3H), 4.09 - 3.87 (m, 1H), 3.33 - 3.10 (m, 1H), 2.23 - 2.02 (m, 1H), 2.00 - 1.71 (m, 2H), 1.56 (s, 1H), 1.44 (s, 9H), 1.28 (t, J = 7.2 Hz, 3H); M/Z: 459, 461 [M+H] ⁺ , ESI ⁺ , RT = 3.83 (S4).

ＬｉＯＨ（０．７８ｇ、３１．１ｍｍｏｌ）を、ＥｔＯＨ（８０ｍＬ）およびＨ_２Ｏ（２０ｍＬ）中の１－ｔｅｒｔ－ブチル２－エチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］ピペリジン－１，２－ジカルボキシレート（７．１ｇ、１５．６ｍｍｏｌ）の溶液に添加し、混合物を室温で３時間の間撹拌した。反応混合物を真空中で濃縮し、Ｈ_２Ｏ（５０ｍＬ）中に再溶解させ、ＤＣＭ（２×１００ｍＬ）で抽出した。水性層を次いで、２ＭのＨＣｌ水溶液を使用してｐＨ２に酸性化し、ＥｔＯＡｃ（３×１００ｍＬ）で抽出した。合わせた有機抽出物をブライン（１００ｍＬ）で洗浄し、無水Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（８７％の純度、５．６０ｇ、１１．３ｍｍｏｌ、７３％の収率）白色の固体として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (d, J = 7.3 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.03 (dd, J = 11.4, 2.8 Hz, 1H), 6.83 - 6.75 (m, 1H), 4.59 - 4.54 (m, 2H), 3.93 (s, 1H), 3.73 (d, J = 54.2 Hz, 1H), 3.13 - 2.94 (m, 1H), 2.06 - 1.87 (m, 2H), 1.61 (d, J = 12.2 Hz, 1H), 1.56 - 1.43 (m, 1H), 1.37 (s, 10H); M/Z: 429, 431 [M+H], ESI⁺, RT = 0.91 min (S1). Intermediate 22 (Step 10.c): (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-2-carboxylic acid

LiOH (0.78 g, 31.1 mmol) was _added to a solution of 1-tert-butyl 2-ethyl(2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1,2-dicarboxylate (7.1 g, 15.6 mmol) in EtOH (80 mL) and H _{2 O (20 mL) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo, redissolved in H 2} O (50 mL) and extracted with DCM (2×100 mL). The aqueous layer was then acidified to pH 2 using 2M aqueous HCl and extracted with EtOAc (3×100 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous _Na2SO4 , _and concentrated in vacuo to give the title compound (87% purity, 5.60 g, 11.3 mmol, 73% yield) as a white solid; ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.02 (d, J = 7.3 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.03 (dd, J = 11.4, 2.8 Hz, 1H), 6.83 - 6.75 (m, 1H), 4.59 - 4.54 (m, 2H), 3.93 (s, 1H), 3.73 (d, J = 54.2 Hz, 1H), 3.13 - 2.94 (m, 1H), 2.06 - 1.87 (m, 2H), 1.61 (d, J = 12.2 Hz, 1H), 1.56 - 1.43 (m, 1H), 1.37 (s, 10H); M/Z: 429, 431 [M+H], ESI ⁺ , RT = 0.91 min (S1).

The intermediates in Table 4 were synthesized according to general route 10 using the corresponding starting materials as exemplified by intermediate 22.

中間体２６：ｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－（ヒドラジンカルボニル）ピペリジン－１－カルボキシレート

ＤＭＦ（８０ｍＬ）中の（２Ｒ，５Ｓ）－１－［（ｔｅｒｔ－ブトキシ）カルボニル］－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］ピペリジン－２－カルボン酸（８．４３ｇ、１９．２ｍｍｏｌ、中間体２２）およびＨＡＴＵ（８．７５ｇ、２３．０ｍｍｏｌ）の溶液に、ＤＩＰＥＡ（４．０ｍＬ、２３．０ｍｍｏｌ）を添加し、室温でＮ_２下にて３０分間撹拌した。結果として生じた溶液を、ＤＭＦ（４０ｍＬ）中のＮＨ_２－ＮＨ_２・Ｈ_２Ｏ（１．９ｍＬ、３８．３ｍｍｏｌ）の溶液に、カニューレを介して滴下により添加し、室温で３０分間撹拌した。反応混合物をＥｔＯＡｃ（１５０ｍＬ）で希釈し、Ｈ_２Ｏ（４×１００ｍＬ）で洗浄した。合わせた有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中で濃縮し、シリカゲル（ＤＣＭ中０～１０％のＭｅＯＨ）上のクロマトグラフィーによって精製することで、標題化合物が（４．５７ｇ、１０．３ｍｍｏｌ、５４％の収率）白色の固体として得られた；¹H NMR (400 MHz, chloroform-d) δ 7.35 - 7.27 (m, 2H), 6.88 - 6.58 (m, 3H), 4.75 (s, 1H), 4.45 (d, J = 3.8 Hz, 2H), 4.12 (s, 2H), 3.88 (s, 2H), 3.09 (d, J = 13.2 Hz, 1H), 2.21 - 2.12 (m, 1H), 1.86 (s, 2H), 1.69 (ddt, J = 17.8, 14.0, 6.1 Hz, 1H), 1.44 (s, 9H); M/Z: 345, 347 [M-Boc+H]⁺, ESI⁺, RT = 0.82 (S2). Scheme for Route 11

Intermediate 26: tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(hydrazinecarbonyl)piperidine-1-carboxylate

To a solution of (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-2-carboxylic acid (8.43 g, 19.2 mmol, intermediate 22) and _{HATU (8.75 g, 23.0 mmol) in DMF (80 mL) was added DIPEA (4.0 mL, 23.0 mmol) and stirred at room temperature under N2 for 30 min. The resulting solution was added dropwise via cannula to a solution of NH2-NH2.H2O ( 1.9 mL} , 38.3 mmol) in DMF (40 mL) and stirred at room temperature for 30 min. The reaction mixture was diluted with EtOAc (150 mL) and washed with _H2O (4 x 100 mL). The combined organic extracts were dried over _MgSO4 , concentrated in vacuo, and purified by chromatography on silica gel (0-10% MeOH in DCM) to give the title compound (4.57 g, 10.3 mmol, 54% yield) as a white solid; ^1H NMR (400 MHz, chloroform-d) δ 7.35 - 7.27 (m, 2H), 6.88 - 6.58 (m, 3H), 4.75 (s, 1H), 4.45 (d, J = 3.8 Hz, 2H), 4.12 (s, 2H), 3.88 (s, 2H), 3.09 (d, J = 13.2 Hz, 1H), 2.21 - 2.12 (m, 1H), 1.86 (s, 2H), 1.69 (ddt, J = 17.8, 14.0, 6.1 Hz, 1H), 1.44 (s, 9H); M/Z: 345, 347 [M-Boc+H] ⁺ , ESI ⁺ , RT = 0.82 (S2).

The intermediates in Table 5 were synthesized according to general route 11 using the corresponding starting materials as exemplified by intermediate 26.

Scheme for Route 12

Ｈ_２Ｏ（１０ｍＬ）および１，４－ジオキサン（４０ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－（ヒドラジンカルボニル）ピペリジン－１－カルボキシレート（３．５０ｇ、７．８７ｍｍｏｌ、中間体２６）およびＮａＨＣＯ_３（９９１ｍｇ、１１．８ｍｍｏｌ）の溶液に、ＢｒＣＮ（８３３ｍｇ、７．８７ｍｍｏｌ）を添加し、混合物を室温で１２時間の間撹拌した。反応混合物をＨ_２Ｏ（６０ｍＬ）で希釈し、ＥｔＯＡｃ（３×６０ｍＬ）で抽出した。合わせた有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（２．３０ｇ、４．６５ｍｍｏｌ、５９％の収率）白色の固体として得られた；¹H NMR (400 MHz, chloroform-d) δ 7.33 (t, J = 8.6 Hz, 1H), 6.88 - 6.64 (m, 3H), 5.48 (s, 1H), 4.95 (s, 2H), 4.53 - 4.40 (m, 2H), 4.22 - 4.01 (m, 2H), 3.15 (s, 1H), 2.23 - 1.83 (m, 4H), 1.46 (s, 9H); M/Z: 470, 472 [M+H]⁺, ESI⁺, RT = 0.87 (S2). Step 12. a: tert-Butyl (2R,5S)-2-(5-amino-1,3,4-oxadiazol-2-yl)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]piperidine-1-carboxylate

To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(hydrazinecarbonyl)piperidine-1-carboxylate (3.50 g, 7.87 mmol, intermediate 26) and NaHCO ₃ (991 _mg , 11.8 mmol) in H 2 O (10 mL) and 1,4-dioxane (40 mL) was added BrCN (833 mg, 7.87 mmol) and the mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with H ₂ O (60 mL) and extracted with EtOAc (3×60 mL). The combined organic extracts were dried over _MgSO4 and concentrated in vacuo to give the title compound (2.30 g, 4.65 mmol, 59% yield) as a white solid; ^1H NMR (400 MHz, chloroform-d) δ 7.33 (t, J = 8.6 Hz, 1H), 6.88 - 6.64 (m, 3H), 5.48 (s, 1H), 4.95 (s, 2H), 4.53 - 4.40 (m, 2H), 4.22 - 4.01 (m, 2H), 3.15 (s, 1H), 2.23 - 1.83 (m, 4H), 1.46 (s, 9H); M/Z: 470, 472 [M+H] ⁺ , ESI ⁺ , RT = 0.87 (S2).

無水ＡＣＮ（３５ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－２－（５－アミノ－１，３，４－オキサジアゾール－２－イル）－５－［［２－（４－クロロ－３－フルオロ－フェノキシ）アセチル］アミノ］ピペリジン－１－カルボキシレート（２．３０ｇ、４．６５ｍｍｏｌ）の溶液に、ＣｕＢｒ（３．１６ｇ、１４．０ｍｍｏｌ）を添加し、混合物を室温で５分間撹拌した。亜硝酸ｔｅｒｔ－ブチル（１．９ｍＬ、１４．０ｍｍｏｌ）を添加し、混合物を室温で１６時間の間、次いで４０℃で１２時間の間撹拌した。反応混合物を真空中で濃縮し、残留物をロッシェル塩（１５０ｍＬ）で希釈し、ＥｔＯＡｃ（３×１５０ｍＬ）で抽出した。合わせた有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中で濃縮し、シリカゲル（ヘプタン中１２～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（１．１０ｇ、２．０３ｍｍｏｌ、４３％の収率）淡黄色の固体として得られた；¹H NMR (500 MHz, chloroform-d) δ 7.33 (t, J = 8.6 Hz, 1H), 6.87 - 6.71 (m, 2H), 6.67 (ddd, J = 8.9, 2.8, 1.1 Hz, 1H), 5.77 - 5.37 (m, 1H), 4.57 - 4.41 (m, 2H), 4.27 - 3.98 (m, 2H), 3.35 - 2.95 (m, 1H), 2.29 - 2.12 (m, 1H), 2.07 - 1.79 (m, 3H), 1.46 (s, 9H); M/Z: 433, 435 [M-Boc+H]⁺, ESI⁺, RT = 1.05 (S2). Intermediate 31 (Step 12.b): tert-Butyl (2R,5S)-2-(5-bromo-1,3,4-oxadiazol-2-yl)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]piperidine-1-carboxylate

To a solution of tert-butyl (2R,5S)-2-(5-amino-1,3,4-oxadiazol-2-yl)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]piperidine-1-carboxylate (2.30 g, 4.65 mmol) in anhydrous ACN (35 mL) was added CuBr (3.16 g, 14.0 mmol) and the mixture was stirred at room temperature for 5 min. tert-Butyl nitrite (1.9 mL, 14.0 mmol) was added and the mixture was stirred at room temperature for 16 h and then at 40° C. for 12 h. The reaction mixture was concentrated in vacuo and the residue was diluted with Rochelle's salt (150 mL) and extracted with EtOAc (3×150 mL). The combined organic extracts were dried over _MgSO4 , concentrated in vacuo, and purified by chromatography on silica gel (12-100% EtOAc in heptane) to give the title compound (1.10 g, 2.03 mmol, 43% yield) as a pale yellow solid; ^1H NMR (500 MHz, chloroform-d) δ 7.33 (t, J = 8.6 Hz, 1H), 6.87 - 6.71 (m, 2H), 6.67 (ddd, J = 8.9, 2.8, 1.1 Hz, 1H), 5.77 - 5.37 (m, 1H), 4.57 - 4.41 (m, 2H), 4.27 - 3.98 (m, 2H), 3.35 - 2.95 (m, 1H), 2.29 - 2.12 (m, 1H), 2.07 - 1.79 (m, 3H), 1.46 (s, 9H); M/Z: 433, 435 [M-Boc+H] ⁺ , ESI ⁺ , RT = 1.05 (S2).

The intermediates in Table 6 were synthesized according to general route 12 using the corresponding starting materials as exemplified by intermediate 31.

Scheme for Route 13

無水ＤＭＦ（４ｍＬ）中の２－（４－クロロ－３－フルオロフェノキシ）酢酸（２５０ｍｇ、１．２２ｍｍｏｌ）の溶液に、ＨＡＴＵ（５５８ｍｇ、１．４７ｍｍｏｌ）およびＤＩＰＥＡ（０．３２ｍＬ、１．８３ｍｍｏｌ）を添加し、室温で１０分間撹拌した。１－ｔｅｒｔ－ブチル２－エチル（２Ｒ，４Ｓ）－４－アミノピロリジン－１，２－ジカルボキシレート（２９９ｍｇ、１．２２ｍｍｏｌ）を添加し、混合物を室温で４５分間撹拌した。反応混合物をＥｔＯＡｃ（５０ｍＬ）とＨ_２Ｏ（３０ｍＬ）との間で分配し、有機層を単離し、ブラインで洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～７０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（８７％の純度、５０５ｍｇ、１．０２ｍｍｏｌ、８３％の収率）オフホワイトの固体として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 8.38 (d, J = 6.7 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.06 (dd, J = 11.4, 2.8 Hz, 1H), 6.89 - 6.80 (m, 1H), 4.54 (s, 2H), 4.40 - 4.26 (m, 2H), 3.67 (d, J = 11.1 Hz, 3H), 3.64 - 3.52 (m, 1H), 3.28 - 3.16 (m, 1H), 2.30 - 2.15 (m, 1H), 2.09 (dt, J = 12.7, 6.1 Hz, 1H), 1.37 (d, J = 22.2 Hz, 9H); M/Z: 331, 333 [M-Boc+H]⁺, ESI⁺, RT = 0.97 (S2). Step 13. a: 1-tert-butyl 2-ethyl (2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]pyrrolidine-1,2-dicarboxylate

To a solution of 2-(4-chloro-3-fluorophenoxy)acetic acid (250 mg, 1.22 mmol) in anhydrous DMF (4 mL) was added HATU (558 mg, 1.47 mmol) and DIPEA (0.32 mL, 1.83 mmol) and stirred at room temperature for 10 min. 1-tert-Butyl 2-ethyl(2R,4S)-4-aminopyrrolidine-1,2-dicarboxylate (299 mg, 1.22 mmol) was added and the mixture was stirred at room temperature for 45 min. The reaction mixture was partitioned between EtOAc (50 mL) and H ₂ O (30 mL) and the organic layer was isolated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-70% EtOAc in heptane) to give the title compound (87% purity, 505 mg, 1.02 mmol, 83% yield) as an off-white solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.38 (d, J = 6.7 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.06 (dd, J = 11.4, 2.8 Hz, 1H), 6.89 - 6.80 (m, 1H), 4.54 (s, 2H), 4.40 - 4.26 (m, 2H), 3.67 (d, J = 11.1 Hz, 3H), 3.64 - 3.52 (m, 1H), 3.28 - 3.16 (m, 1H), 2.30 - 2.15 (m, 1H), 2.09 (dt, J = 12.7, 6.1 Hz, 1H), 1.37 (d, J = 22.2 Hz, 9H); M/Z: 331, 333 [M-Boc+H] ⁺ , ESI ⁺ , RT = 0.97 (S2).

ＭｅＯＨ（２ｍＬ）：ＴＨＦ（２ｍＬ）：Ｈ_２Ｏ（２ｍＬ）中の１－ｔｅｒｔ－ブチル２－エチル（２Ｒ，４Ｓ）－４－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］ピロリジン－１，２－ジカルボキシレート（８７％の純度、５０５ｍｇ、１．０２ｍｍｏｌ）の溶液に、ＬｉＯＨ・Ｈ_２Ｏ（５３ｍｇ、１．２２ｍｍｏｌ）を添加し、混合物を室温で１７時間の間撹拌した。反応混合物をＥｔＯＡｃ（３０ｍＬ）と１ＭのＨＣｌ水溶液（１０ｍＬ）との間で分配した。有機層を単離し、ブラインで洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（８０％の純度、４０１ｍｇ、０．７７０ｍｍｏｌ、７６％の収率）無色の油状物として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 8.37 (d, J = 6.9 Hz, 1H), 7.54 - 7.45 (m, 1H), 7.06 (dd, J = 11.4, 2.8 Hz, 1H), 6.84 (dt, J = 9.0, 1.4 Hz, 1H), 4.54 (s, 2H), 4.35 (dq, J = 12.1, 6.5 Hz, 1H), 4.26 - 4.15 (m, 1H), 3.64 - 3.52 (m, 1H), 3.20 (dq, J = 15.0, 5.9, 5.5 Hz, 1H), 2.28 - 2.12 (m, 1H), 2.12 - 2.01 (m, 1H), 1.37 (d, J = 15.9 Hz, 9H); M/Z: 317, 319 [M-Boc+H]⁺, ESI⁺, RT = 0.86 (S2). Intermediate 34 (Step 13.b): (2R,4S)-1-[(tert-butoxy)carbonyl]-4-[2-(4-chloro-3-fluorophenoxy)acetamido]pyrrolidine-2-carboxylic acid

To a solution of 1-tert-butyl 2-ethyl ₍ 2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]pyrrolidine-1,2-dicarboxylate (87% purity, 505 mg, 1.02 mmol) in MeOH (2 mL):THF (2 mL):H ₂ O (2 mL) was added LiOH.H 2 O (53 mg, 1.22 mmol) and the mixture was stirred at room temperature for 17 h. The reaction mixture was partitioned between EtOAc (30 mL) and 1 M aqueous HCl (10 mL). The organic layer was isolated, washed with brine, dried over _MgSO4 , and concentrated in vacuo to give the title compound (80% purity, 401 mg, 0.770 mmol, 76% yield) as a colorless oil; ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.37 (d, J = 6.9 Hz, 1H), 7.54 - 7.45 (m, 1H), 7.06 (dd, J = 11.4, 2.8 Hz, 1H), 6.84 (dt, J = 9.0, 1.4 Hz, 1H), 4.54 (s, 2H), 4.35 (dq, J = 12.1, 6.5 Hz, 1H), 4.26 - 4.15 (m, 1H), 3.64 - 3.52. (m, 1H), 3.20 (dq, J = 15.0, 5.9, 5.5 Hz, 1H), 2.28 - 2.12 (m, 1H), 2.12 - 2.01 (m, 1H), 1.37 (d, J = 15.9 Hz, 9H); [M-Boc+H] ⁺ , ESI ⁺ , RT = 0.86 (S2).

Scheme for Route 14

２－フルオロピリジン（１．６ｍＬ、１８．２ｍｍｏｌ）およびＴＭＳ－ＣＦ_３（２．７ｍＬ、１８．２ｍｍｏｌ）を順次に、ＥｔＯＡｃ（５０ｍＬ）中のｔｅｒｔ－ブチル４－ヒドロキシブタノエート（１．０ｇ、６．０５ｍｍｏｌ）、ＡｇＯＴｆ（４．６９ｇ、１８．２ｍｍｏｌ）、セレクトフルオル（３．２２ｇ、９．０８ｍｍｏｌ）およびＫＦ（１．４１ｇ、２４．２ｍｍｏｌ）の溶液に、箔で覆われたフラスコの中でＮ_２下にて滴下により添加し、混合物を室温で２４時間の間撹拌した。反応混合物をセライトに通して濾過し、ＥｔＯＡｃ（３０ｍＬ）で洗浄し、真空中で濃縮した。残留物をシリカゲル（ヘプタン中５～３０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（９０％の純度、３３０ｍｇ、１．３０ｍｍｏｌ、２１％の収率）無色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) δ 4.02 (t, J = 6.2 Hz, 2H), 2.37 (t, J = 7.2 Hz, 2H), 1.98 (p, J = 6.7 Hz, 2H), 1.46 (s, 9H); ¹⁹F NMR (376 MHz, chloroform-d) δ -60.81 (3F, s). Step 14. a: tert-butyl 4-(trifluoromethoxy)butanoate

2-Fluoropyridine (1.6 mL, 18.2 mmol) and TMS-CF ₃ (2.7 mL, 18.2 mmol) were added dropwise successively to a solution of tert-butyl 4-hydroxybutanoate (1.0 g, 6.05 mmol), AgOTf (4.69 g, 18.2 mmol), Selectfluor (3.22 g, 9.08 mmol) and KF (1.41 g, 24.2 mmol) in EtOAc (50 mL) in a foil-covered flask under N ₂ and the mixture was stirred at room temperature for 24 h. The reaction mixture was filtered through Celite, washed with EtOAc (30 mL) and concentrated in vacuo. The residue was purified by chromatography on silica gel (5-30% EtOAc in heptane) to give the title compound (90% purity, 330 mg, 1.30 mmol, 21% yield) as a colorless oil; ¹ H NMR (400 MHz, chloroform-d) δ 4.02 (t, J = 6.2 Hz, 2H), 2.37 (t, J = 7.2 Hz, 2H), 1.98 (p, J = 6.7 Hz, 2H), 1.46 (s, 9H); ¹⁹ F NMR (376 MHz, chloroform-d) δ -60.81 (3F, s).

１，４－ジオキサン（５ｍＬ）中４ＭのＨＣｌ中のｔｅｒｔ－ブチル４－（トリフルオロメトキシ）ブタノエート（３３０ｍｇ、１．４５ｍｍｏｌ）の溶液を室温で２時間の間撹拌した。反応混合物を真空中で濃縮することで、標題化合物が（８３％の純度、７３ｍｇ、０．３５２ｍｍｏｌ、２４％の収率）黄色の油状物として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 12.20 (s, 1H), 4.32 (td, J = 6.4, 4.2 Hz, 1H), 4.09 (t, J = 6.5 Hz, 2H), 2.32 (td, J = 7.2, 2.8 Hz, 3H), 1.95 - 1.80 (m, 3H), 1.40 (s, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ -58.82 (3F, s). Intermediate 35 (Step 14.b): 4-(Trifluoromethoxy)butanoic Acid

A solution of tert-butyl 4-(trifluoromethoxy)butanoate (330 mg, 1.45 mmol) in 4 M HCl in 1,4-dioxane (5 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo to give the title compound (83% purity, 73 mg, 0.352 mmol, 24% yield) as a yellow oil; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.20 (s, 1H), 4.32 (td, J = 6.4, 4.2 Hz, 1H), 4.09 (t, J = 6.5 Hz, 2H), 2.32 (td, J = 7.2, 2.8 Hz, 3H), 1.95 - 1.80 (m, 3H), 1.40 (s, 1H); ¹⁹ F NMR (376 MHz, DMSO-d ₆ ) δ -58.82 (3F, s).

Scheme for Route 15

ＥｔＯＡｃ（３０ｍＬ）中のｔｅｒｔ－ブチル３－ヒドロキシ－３－メチルアゼチジン－１－カルボキシレート（１．００ｇ、５．３４ｍｍｏｌ）の溶液に室温でＮ_２下にて箔で覆われたフラスコの中で、ＡｇＯＴｆ（４．１３ｇ、１６．０ｍｍｏｌ）、ＫＦ（１．２４ｇ、２１．４ｍｍｏｌ）およびセレクトフルオル（２．８４ｇ、８．０１ｍｍｏｌ）を添加し、室温で５分間撹拌した。２－フルオロピリジン（１．４ｍＬ、１６．０ｍｍｏｌ）およびＴＭＳ－ＣＦ_３（２．４ｍＬ、１６．０ｍｍｏｌ）を次いで添加し、混合物を室温で３時間の間撹拌した。反応混合物をセライトに通して濾過し、ＥｔＯＡｃ（１００ｍＬ）で洗浄して、濾液を真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～５０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（１６３ｍｇ、０．６３９ｍｍｏｌ、１２％の収率）無色の油状物として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 4.02 (d, J = 9.5 Hz, 2H), 3.91 (d, J = 9.6 Hz, 2H), 1.67 (s, 3H), 1.39 (s, 9H). Step 15. a: tert-butyl 3-methyl-3-(trifluoromethoxy)azetidine-1-carboxylate

To a solution of tert-butyl 3-hydroxy-3-methylazetidine-1-carboxylate (1.00 g, 5.34 mmol) in EtOAc (30 mL) in a foil-covered flask under _N2 at room temperature was added AgOTf (4.13 g, 16.0 mmol), KF (1.24 g, 21.4 mmol) and Selectfluor (2.84 g, 8.01 mmol) and stirred at room temperature for 5 min. 2-Fluoropyridine (1.4 mL, 16.0 mmol) and TMS- _CF3 (2.4 mL, 16.0 mmol) were then added and the mixture was stirred at room temperature for 3 h. The reaction mixture was filtered through Celite, washed with EtOAc (100 mL) and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (0-50% EtOAc in heptane) to give the title compound (163 mg, 0.639 mmol, 12% yield) as a colorless oil; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 4.02 (d, J = 9.5 Hz, 2H), 3.91 (d, J = 9.6 Hz, 2H), 1.67 (s, 3H), 1.39 (s, 9H).

無水１，４－ジオキサン（３ｍＬ）中のｔｅｒｔ－ブチル３－メチル－３－（トリフルオロメトキシ）アゼチジン－１－カルボキシレート（１６０ｍｇ、０．６２７ｍｍｏｌ）の溶液に、１，４－ジオキサン（１．０ｍＬ、４．００ｍｍｏｌ）中４ＭのＨＣｌを添加し、混合物を室温で２０時間の間撹拌した。反応混合物を真空中で濃縮することで、標題化合物が（１１６ｍｇ、０．６０５ｍｍｏｌ、９７％の収率）白色の粉末として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 9.18 (s, 2H), 4.22 (d, J = 12.2 Hz, 2H), 4.07 (d, J = 12.5 Hz, 2H), 1.74 (s, 3H); M/Z: 156 [M+H]⁺, ESI⁺, RT = 0.37 (S2). Intermediate 36 (Step 15.b): 3-Methyl-3-(trifluoromethoxy)azetidine hydrochloride

To a solution of tert-butyl 3-methyl-3-(trifluoromethoxy)azetidine-1-carboxylate (160 mg, 0.627 mmol) in anhydrous 1,4-dioxane (3 mL) was added 4 M HCl in 1,4-dioxane (1.0 mL, 4.00 mmol) and the mixture was stirred at room temperature for 20 h. The reaction mixture was concentrated in vacuo to give the title compound (116 mg, 0.605 mmol, 97% yield) as a white powder; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.18 (s, 2H), 4.22 (d, J = 12.2 Hz, 2H), 4.07 (d, J = 12.5 Hz, 2H), 1.74 (s, 3H); M/Z: 156 [M+H] ⁺ , ESI ⁺ , RT = 0.37 (S2).

Scheme for Route 16

無水ＴＨＦ（５ｍＬ）中のベンジルヒドラジンカルボキシレート（４０６μＬ、２．５２ｍｍｏｌ）およびピリジン（４０７μＬ、５．０３ｍｍｏｌ）の溶液に、無水ＴＨＦ（３ｍＬ）中の４－ニトロフェニルカルボノクロリデート（５５８ｍｇ、２．７７ｍｍｏｌ）の溶液を添加し、混合物をＮ_２下にて室温で１時間の間撹拌した。混合物を次いで、無水ＴＨＦ（５ｍＬ）中の３－（トリフルオロメトキシ）アゼチジン塩酸塩（４６９ｍｇ、２．６４ｍｍｏｌ）およびＤＩＰＥＡ（１．３ｍＬ、７．５５ｍｍｏｌ）の溶液にゆっくり添加し、室温でＮ_２下にて３０分間撹拌した。反応混合物を飽和ＮａＨＣＯ_３水溶液（１０ｍＬ）でクエンチし、ＥｔＯＡｃ（３×１０ｍＬ）で抽出した。合わせた有機抽出物をＨ_２Ｏ（３０ｍＬ）およびブライン（３０ｍＬ）で洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をＥｔＯＡｃ（１０ｍＬ）中に溶解させ、飽和Ｋ_２ＣＯ_３水溶液（３×１０ｍＬ）で洗浄した。有機層をＭｇＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（９２％の純度、７７０ｍｇ、２．１３ｍｍｏｌ、８５％の収率）オフホワイトの粉末として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (s, 1H), 8.51 (s, 1H), 7.41 - 7.26 (m, 5H), 5.21 - 5.11 (m, 1H), 5.07 (s, 2H), 4.27 - 4.17 (m, 2H), 3.92 - 3.83 (m, 2H); M/Z: 334 [M+H]⁺, ESI⁺, RT = 0.74 (S2). Step 16. a: ({[(benzyloxy)carbonyl]amino}amino)[3-(trifluoromethoxy)azetidin-1-yl]methanone

To a solution of benzylhydrazine carboxylate (406 μL, 2.52 mmol) and pyridine (407 μL, 5.03 mmol) in anhydrous THF (5 mL) was added a solution of 4-nitrophenyl carbonochloridate (558 mg, 2.77 mmol) in anhydrous THF (3 mL) and the mixture was stirred at room temperature under _N for 1 h. The mixture was then slowly added to a solution of 3-(trifluoromethoxy)azetidine hydrochloride (469 mg, 2.64 mmol) and DIPEA ( _1.3 mL, 7.55 mmol) in anhydrous THF (5 mL) and stirred at room temperature under _N for ₃₀ min. The reaction mixture was quenched with saturated aqueous NaHCO (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with _H O (30 mL) and brine (30 mL), dried over MgSO and concentrated in vacuo. The residue was dissolved in EtOAc (10 mL) and washed with saturated aqueous K ₂ CO ₃ (3×10 mL). The organic layer was dried over _MgSO4 and concentrated in vacuo to give the title compound (92% purity, 770 mg, 2.13 mmol, 85% yield) as an off-white powder; ^1H NMR (500 MHz, DMSO- _d6 ) δ 9.00 (s, 1H), 8.51 (s, 1H), 7.41 - 7.26 (m, 5H), 5.21 - 5.11 (m, 1H), 5.07 (s, 2H), 4.27 - 4.17 (m, 2H), 3.92 - 3.83 (m, 2H); M/Z: 334 [M+H] ⁺ , ESI ⁺ , RT = 0.74 (S2).

無水ＥｔＯＨ（２１ｍＬ）中の（｛［（ベンジルオキシ）カルボニル］アミノ｝アミノ）［３－（トリフルオロメトキシ）アゼチジン－１－イル］メタノン（９２％の純度、７６７ｍｇ、２．１２ｍｍｏｌ）の溶液にＮ_２下で、１０％のＰｄ／Ｃ（２２６ｍｇ、０．２１２ｍｍｏｌ）を添加し、混合物をＨ_２下にて室温で４時間の間撹拌した。反応混合物をセライトのパッドに通して濾過し、温ＥｔＯＨ（３×１５ｍＬ）で洗浄し、真空中で濃縮することで、標題化合物が（８８％の純度、２６９ｍｇ、１．１９ｍｍｏｌ、５６％の収率）茶色の固体として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 7.65 (s, 1H), 5.18 - 5.07 (m, 1H), 4.23 - 4.11 (m, 2H), 3.88 (s, 2H), 3.86 - 3.76 (m, 2H). Intermediate 37 (Step 16.b): 3-(trifluoromethoxy)azetidine-1-carbohydrazide

To a solution of ({[(benzyloxy)carbonyl]amino}amino)[3-(trifluoromethoxy)azetidin-1-yl]methanone (92% purity, 767 mg, 2.12 mmol) in absolute EtOH (21 mL) under _N2 was added 10% Pd/C (226 mg, 0.212 mmol) and the mixture was stirred at room temperature under _H2 for 4 h. The reaction mixture was filtered through a pad of Celite, washed with warm EtOH (3×15 mL) and concentrated in vacuo to give the title compound (88% purity, 269 mg, 1.19 mmol, 56% yield) as a brown solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.65 (s, 1H), 5.18 - 5.07 (m, 1H), 4.23 - 4.11 (m, 2H), 3.88 (s, 2H), 3.86 - 3.76 (m, 2H).

Scheme for Route 17

ＤＣＭ（２０ｍＬ）中の３，３，３－トリフルオロプロパン－１－オール（１．００ｇ、８．７７ｍｍｏｌ）を、ＴＨＦ（５０ｍＬ）中のＣＤＩ（２．１３ｇ、１３．１ｍｍｏｌ）の溶液に０℃でＮ_２下にて添加し、混合物を室温で２時間の間撹拌した。反応混合物を真空中で濃縮し、残留物をシリカゲル（ヘプタン中１２～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（９２％の純度、８２７ｍｇ、３．８９ｍｍｏｌ、４４％の収率）無色の油状物として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 8.25 (s, 1H), 7.58 (s, 1H), 7.12 - 7.08 (m, 1H), 4.64 - 4.58 (m, 2H), 2.87 (tp, J = 11.3, 5.8 Hz, 2H). Step 17. a: 3,3,3-trifluoropropylimidazole-1-carboxylate

3,3,3-Trifluoropropan-1-ol (1.00 g, 8.77 mmol) in DCM (20 mL) was added to a solution of CDI (2.13 g, 13.1 mmol) in THF (50 mL) at 0 °C under _N2 and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo and the residue was purified by chromatography on silica gel (12-100% EtOAc in heptane) to give the title compound (92% purity, 827 mg, 3.89 mmol, 44% yield) as a colorless oil; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.25 (s, 1H), 7.58 (s, 1H), 7.12 - 7.08 (m, 1H), 4.64 - 4.58 (m, 2H), 2.87 (tp, J = 11.3, 5.8 Hz, 2H).

ＤＣＭ（１４０ｍＬ）中の３，３，３－トリフルオロプロピルイミダゾール－１－カルボキシレート（９２％の純度、８．９５ｇ、３９．６ｍｍｏｌ）の溶液を、ＮＨ_２ＮＨ_２・Ｈ_２Ｏ（７．８ｍＬ、０．１５８ｍｏｌ）で処理し、混合物を室温で１時間の間撹拌した。反応混合物をＩＰＡ（３０ｍＬ）およびＨ_２Ｏ（５０ｍＬ）で希釈し、有機層を単離し、飽和ＮａＨＣＯ_３水溶液（５０ｍＬ）およびブライン（５０ｍＬ）で順次に洗浄した。有機層をＭｇＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（９０％の純度、４．０９ｇ、２１．４ｍｍｏｌ、５４％の収率）淡黄色の油状物として得られた；¹H NMR (500 MHz, chloroform-d) δ 2.28 - 2.57 (m, 2H), 3.69 (s, 2H), 4.19 - 4.36 (m, 2H), 5.99 (s, 1H). Intermediate 38 (Step 17.b): (3,3,3-trifluoropropoxy)carbohydrazide

A solution of 3,3,3-trifluoropropylimidazole-1-carboxylate (92% purity, 8.95 g, 39.6 mmol) in DCM (140 mL) was treated with NH ₂ NH ₂ ·H ₂ O (7.8 mL, 0.158 mol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with IPA (30 mL) and H ₂ O (50 mL) and the organic layer was isolated and washed successively with saturated aqueous NaHCO ₃ (50 mL) and brine (50 mL). The organic layer was dried over _MgSO4 and concentrated in vacuo to give the title compound (90% purity, 4.09 g, 21.4 mmol, 54% yield) as a pale yellow oil; ^1H NMR (500 MHz, chloroform-d) δ 2.28 - 2.57 (m, 2H), 3.69 (s, 2H), 4.19 - 4.36 (m, 2H), 5.99 (s, 1H).

Scheme for Route 18

無水ＡＣＮ（２０ｍＬ）中の２－（ベンジルオキシ）エタノール（１．５０ｇ、９．８６ｍｍｏｌ）の溶液に、ＣｕＩ（４６９ｍｇ、２．４６ｍｍｏｌ）を添加し、混合物を５０℃で５分間撹拌した。無水ＡＣＮ（１０ｍＬ）中の２，２－ジフルオロ－２－（フルオロスルホニル）酢酸（２．６３ｇ、１４．８ｍｍｏｌ）の溶液を、２５分かけて滴下により添加し、結果として生じた混合物を５０℃で１時間の間撹拌した。反応混合物を真空中で濃縮し、残留物をＥｔＯＡｃ中に溶解させた。結果として生じた沈殿物を真空下で濾過し、濾液を単離し、真空中で濃縮した。残留物をシリカゲル（ヘプタン中１０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（９０％の純度、６２０ｍｇ、２．７６ｍｍｏｌ、２８％の収率）無色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) δ 7.40 - 7.27 (m, 5H), 6.28 (t, J = 74.8 Hz, 1H), 4.58 (s, 2H), 4.04 - 3.97 (m, 2H), 3.71 - 3.62 (m, 2H); ¹⁹F NMR (376 MHz, chloroform-d) δ -84.27. Step 18. a: {[2-(difluoromethoxy)ethoxy]methyl}benzene

To a solution of 2-(benzyloxy)ethanol (1.50 g, 9.86 mmol) in anhydrous ACN (20 mL) was added CuI (469 mg, 2.46 mmol) and the mixture was stirred at 50° C. for 5 min. A solution of 2,2-difluoro-2-(fluorosulfonyl)acetic acid (2.63 g, 14.8 mmol) in anhydrous ACN (10 mL) was added dropwise over 25 min and the resulting mixture was stirred at 50° C. for 1 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc. The resulting precipitate was filtered under vacuum and the filtrate was isolated and concentrated in vacuo. The residue was purified by chromatography on silica gel (10-100% EtOAc in heptane) to give the title compound (90% purity, 620 mg, 2.76 mmol, 28% yield) as a colorless oil; ¹ H NMR (400 MHz, chloroform-d) δ 7.40 - 7.27 (m, 5H), 6.28 (t, J = 74.8 Hz, 1H), 4.58 (s, 2H), 4.04 - 3.97 (m, 2H), 3.71 - 3.62 (m, 2H); ¹⁹ F NMR (376 MHz, chloroform-d) δ -84.27.

ＴＨＦ（７．５ｍＬ）中の｛［２－（ジフルオロメトキシ）エトキシ］メチル｝ベンゼン（９０％の純度、６２０ｍｇ、２．７６ｍｍｏｌ）および１０％のＰｄ／Ｃ（５８７ｍｇ、０．５５２ｍｍｏｌ）の懸濁液を、Ｈ_２下にて１８時間の間撹拌した。反応混合物をセライトに通して濾過し、ＴＨＦで洗浄した。濾液に１０％のＰｄ／Ｃ（１．４７ｇ、１．３８ｍｍｏｌ）を再投入し、混合物をＨ_２下にて１８時間の間撹拌した。反応混合物をセライトに通して濾過し、ＴＨＦで洗浄して、ＴＨＦ／トルエン中の標題化合物の２．２３％であると推定される粗製溶液が（２．２３：９５．９：１．８３、約１０ｍＬ）得られた；¹H NMR (400 MHz, chloroform-d) δ 6.20 (t, J = 74.9 Hz, 1H), 3.89 - 3.81 (m, 2H), 3.76 - 3.56 (m, 2H). Intermediate 39 (Step 18.b): 2-(Difluoromethoxy)ethan-1-ol

A suspension of {[2-(difluoromethoxy)ethoxy]methyl}benzene (90% purity, 620 mg, 2.76 mmol) and 10% Pd/C (587 mg, 0.552 mmol) in THF (7.5 mL) was stirred under _H2 for 18 h. The reaction mixture was filtered through Celite and washed with THF. The filtrate was recharged with 10% Pd/C (1.47 g, 1.38 mmol) and the mixture was stirred under _H2 for 18 h. The reaction mixture was filtered through Celite and washed with THF to give a crude solution estimated to be 2.23% of the title compound in THF/toluene (2.23:95.9:1.83, ca. 10 mL); ¹ H NMR (400 MHz, chloroform-d) δ 6.20 (t, J = 74.9 Hz, 1H), 3.89 - 3.81 (m, 2H), 3.76 - 3.56 (m, 2H).

Scheme for Route 19

ＤＣＭ（４０ｍＬ）中の２－（エテニルオキシ）エタン－１－オール（１．００ｇ、１１．３ｍｍｏｌ）の溶液に０℃で、Ｅｔ_３Ｎ（４．０ｍＬ、２８．４ｍｍｏｌ）、続いて、滴下により塩化ベンゾイル（２．０ｍＬ、１７．０ｍｍｏｌ）を添加し、混合物を室温で６時間の間撹拌した。反応混合物を０℃に冷却し、１ＭのＨＣｌ水溶液（１０ｍＬ）でクエンチした。水溶液をＤＣＭ（３×２０ｍＬ）で抽出し、合わせた有機抽出物を飽和ＮａＨＣＯ_３水溶液（１５ｍＬ）およびブライン（１５ｍＬ）で逐次に洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（０～８０％のＥｔＯＡｃｉｎヘプタン）上のクロマトグラフィーによって精製することで、標題化合物が（７６０ｍｇ、３．９５ｍｍｏｌ、３５％の収率）清澄な油状物として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 8.00 - 7.93 (m, 2H), 7.70 - 7.61 (m, 1H), 7.58 - 7.49 (m, 2H), 6.55 (dd, J = 14.3, 6.8 Hz, 1H), 4.51 - 4.45 (m, 2H), 4.26 (dd, J = 14.3, 1.9 Hz, 1H), 4.05 - 3.99 (m, 3H). Step 19. a: 2-(ethenyloxy)ethyl benzoate

To a solution of 2-(ethenyloxy)ethan-1-ol (1.00 g, 11.3 mmol) in DCM (40 mL) at 0° C. was added Et ₃ N (4.0 mL, 28.4 mmol) followed by dropwise benzoyl chloride (2.0 mL, 17.0 mmol) and the mixture was stirred at room temperature for 6 h. The reaction mixture was cooled to 0° C. and quenched with 1 M aqueous HCl (10 mL). The aqueous solution was extracted with DCM (3×20 mL) and the combined organic extracts were washed successively with saturated aqueous NaHCO ₃ (15 mL) and brine (15 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-80% EtOAc in heptane) to give the title compound (760 mg, 3.95 mmol, 35% yield) as a clear oil; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.00 - 7.93 (m, 2H), 7.70 - 7.61 (m, 1H), 7.58 - 7.49 (m, 2H), 6.55 (dd, J = 14.3, 6.8 Hz, 1H), 4.51 - 4.45 (m, 2H), 4.26 (dd, J = 14.3, 1.9 Hz, 1H), 4.05 - 3.99 (m, 3H).

ＴＨＦ（２ｍＬ）中の２－（エテニルオキシ）エチルベンゾエート（５０ｍｇ、０．２６０ｍｍｏｌ）の溶液に、ＴＭＳＣＦ_３（７７μＬ、０．５２０ｍｍｏｌ）およびＮａＩ（８６ｍｇ、０．５７２ｍｍｏｌ）を添加し、混合物をＮ_２下にて６５℃で４時間の間撹拌した。反応混合物を室温に冷却し、Ｈ_２Ｏ（５ｍＬ）で希釈し、ＥｔＯＡｃ（３×５ｍＬ）で抽出した。合わせた有機抽出物をブライン（５ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～８０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（６２ｍｇ、０．２４６ｍｍｏｌ、９４％の収率）清澄な油状物として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 8.02 - 7.91 (m, 2H), 7.71 - 7.62 (m, 1H), 7.59 - 7.48 (m, 2H), 4.49 - 4.37 (m, 2H), 4.02 - 3.93 (m, 1H), 3.95 - 3.84 (m, 2H), 1.76 - 1.65 (m, 1H), 1.60 - 1.50 (m, 1H); M/Z: 243 [M+H]⁺, ESI⁺, RT = 1.22 (S1). Step 19. b: 2-(2,2-difluorocyclopropoxy)ethyl benzoate

To a solution of 2-(ethenyloxy)ethyl benzoate (50 mg, 0.260 mmol) in THF (2 mL) was added TMSCF ₃ (77 μL, 0.520 mmol) and NaI (86 mg, 0.572 mmol) and the mixture was stirred under N ₂ at 65° C. for 4 h. The reaction mixture was cooled to room temperature, diluted with H ₂ O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic extracts were washed with brine (5 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-80% EtOAc in heptane) to give the title compound (62 mg, 0.246 mmol, 94% yield) as a clear oil; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.02 - 7.91 (m, 2H), 7.71 - 7.62 (m, 1H), 7.59 - 7.48 (m, 2H), 4.49 - 4.37 (m, 2H), 4.02 - 3.93 (m, 1H), 3.95 - 3.84 (m, 2H), 1.76 - 1.65 (m, 1H), 1.60 - 1.50 (m, 1H); M/Z: 243 [M+H] ⁺ , ESI ⁺ , RT = 1.22 (S1).

２－メチルオキソラン（１ｍＬ）中の２－（２，２－ジフルオロシクロプロポキシ）エチルベンゾエート（６０ｍｇ、０．２４８ｍｍｏｌ）の溶液に、１ＭのＮａＯＨ水溶液（０．９９ｍＬ、０．９９１ｍｍｏｌ）を添加し、混合物を室温で２４時間の間撹拌した。反応混合物をＨ_２Ｏ（３ｍＬ）で希釈し、Ｅｔ_２Ｏ（３×３ｍＬ）で抽出した。合わせた有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中にて室温で濃縮することで、標題化合物が（１７ｍｇ、０．１２３ｍｍｏｌ、５０％の収率）清澄な油状物として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 4.72 (t, J = 5.3 Hz, 1H), 3.91 - 3.84 (m, 1H), 3.59 - 3.49 (m, 4H), 1.71 - 1.59 (m, 1H), 1.54 - 1.43 (m, 1H). Intermediate 40 (Step 19.c): 2-(2,2-difluorocyclopropoxy)ethan-1-ol

To a solution of 2-(2,2-difluorocyclopropoxy)ethyl benzoate (60 mg, 0.248 mmol) in 2-methyloxolane (1 mL) was added 1 M aqueous NaOH (0.99 mL, 0.991 mmol) and the mixture was stirred at room temperature for 24 h. The reaction mixture was diluted with H ₂ O (3 mL) and extracted with Et ₂ O (3×3 mL). The combined organic extracts were dried over _MgSO4 and concentrated in vacuo at room temperature to give the title compound (17 mg, 0.123 mmol, 50% yield) as a clear oil; ^1H NMR (500 MHz, DMSO- _d6 ) δ 4.72 (t, J = 5.3 Hz, 1H), 3.91 - 3.84 (m, 1H), 3.59 - 3.49 (m, 4H), 1.71 - 1.59 (m, 1H), 1.54 - 1.43 (m, 1H).

Scheme for Route 20

ＤＭＦ（４０ｍＬ）中の（１，３－ジオキソイソインドリン－２－イル）カリウム（４．５５ｇ、２４．４ｍｍｏｌ）およびジエチル２，５－ジブロモヘキサンジオエート（４．０ｇ、１１．１ｍｍｏｌ）の混合物を９０℃で４時間の間撹拌し、次いで、室温に冷却させておいた。反応混合物を真空中で濃縮し、残留物をＨ_２Ｏ（１５０ｍＬ）で希釈し、ＥｔＯＡｃ（２×１００ｍＬ）で抽出した。合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮し、分取ＨＰＬＣ（方法５）によって精製することで、標題化合物が（９１％の純度、２．５１ｇ、４．６４ｍｍｏｌ、４２％の収率）黄色の油状物として得られた；¹H NMR (500 MHz, chloroform-d) δ 7.92 - 7.80 (m, 4H), 7.79 - 7.70 (m, 4H), 4.95 - 4.89 (m, 1H), 4.82 - 4.74 (m, 1H), 4.23 - 4.07 (m, 4H), 2.38 - 2.21 (m, 4H), 1.20 - 1.13 (m, 6H); M/Z: 493 [M+H]⁺, ESI⁺, RT = 1.02 (S1). Step 20. a: 1,6-diethyl 2,5-bis(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)hexanedioate

A mixture of (1,3-dioxoisoindolin-2-yl)potassium (4.55 g, 24.4 mmol) and diethyl 2,5-dibromohexanedioate (4.0 g, 11.1 mmol) in DMF (40 mL) was stirred at 90° C. for 4 h and then allowed to cool to room temperature. The reaction mixture was concentrated in vacuo and the residue was diluted with H ₂ O (150 mL) and extracted with EtOAc (2×100 mL). _The combined organic extracts were dried over _Na2SO4 , concentrated in vacuo and purified by preparative HPLC (Method 5) to give the title compound (91% purity, 2.51 g, 4.64 mmol, 42% yield) as a yellow oil; ^1H NMR (500 MHz, chloroform-d) δ 7.92 - 7.80 (m, 4H), 7.79 - 7.70 (m, 4H), 4.95 - 4.89 (m, 1H), 4.82 - 4.74 (m, 1H), 4.23 - 4.07 (m, 4H), 2.38 - 2.21 (m, 4H), 1.20 - 1.13 (m, 6H); M/Z: 493 [M+H] ⁺ , ESI ⁺ , RT = 1.02 (S1).

メチルヒドラジン（０．７３ｍＬ、１３．７２ｍｍｏｌ）を、ＥｔＯＨ（２５ｍＬ）中の１，６－ジエチル２，５－ビス（１，３－ジオキソ－２，３－ジヒドロ－１Ｈ－イソインドール－２－イル）ヘキサンジオエート（２．４０ｇ、４．６４ｍｍｏｌ）の懸濁液に添加し、混合物を還流で６時間の間撹拌した。反応混合物を半濃縮し、０℃に冷却した。固体を真空下で濾過し、濾液を真空中で濃縮した。残留物をＥｔＯＨ（５ｍＬ）中に溶解させ、第１にＥｔＯＨ（２×２０ｍＬ）でフラッシュするとともに第２にＭｅＯＨ中７ＭのＮＨ_３で溶出するＳＣＸ－２カートリッジを使用して精製することで、標題化合物が（８３５ｍｇ、４．４８ｍｍｏｌ、９７％の収率）褐色の油状物として得られた；Ｍ／Ｚ：１８７［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝０．１６（Ｓ１）。 Step 20.b: Ethyl 5-amino-6-oxopiperidine-2-carboxylate

Methylhydrazine (0.73 mL, 13.72 mmol) was added to a suspension of 1,6-diethyl 2,5-bis(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)hexanedioate (2.40 g, 4.64 mmol) in EtOH (25 mL) and the mixture was stirred at reflux for 6 h. The reaction mixture was semi-concentrated and cooled to 0° C. The solids were filtered under vacuum and the filtrate was concentrated in vacuo. The residue was dissolved in EtOH (5 mL) and purified using an SCX-2 cartridge, first flushed with EtOH (2×20 mL) and secondly eluted with 7M NH ₃ in MeOH to give the title compound (835 mg, 4.48 mmol, 97% yield) as a brown oil; M/Z: 187 [M+H] ⁺ , ESI ⁺ , RT=0.16 (S1).

ＤＣＭ（８ｍＬ）中のエチル５－アミノ－６－オキソ－ピペリジン－２－カルボキシレート（７００ｍｇ、３．７６ｍｍｏｌ）およびＤＩＰＥＡ（１．３ｍＬ、７．５２ｍｍｏｌ）の撹拌溶液に０℃で、ＤＣＭ（２ｍＬ）中の２－（４－クロロ－３－フルオロ－フェノキシ）アセチルクロリド（８３８ｍｇ、３．７６ｍｍｏｌ）の溶液を添加し、室温で２時間の間撹拌した。混合物をＤＣＭ（２０ｍＬ）で希釈し、１ＭのＨＣｌ水溶液（２０ｍＬ）で洗浄した。有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮し、分取ＨＰＬＣ（方法５）によって精製することで、標題化合物が（７２％の純度、４３３ｍｇ、０．８３６ｍｍｏｌ、２２％の収率）白色の固体として得られた；¹H NMR (400 MHz, chloroform-d) δ 7.41 - 7.28 (m, 2H), 6.80 - 6.74 (m, 1H), 6.73 - 6.66 (m, 1H), 6.33 - 6.25 (m, 1H), 4.51 - 4.46 (m, 2H), 4.35 - 4.22 (m, 2H), 4.20 - 4.11 (m, 1H), 2.71 - 2.49 (m, 1H), 2.47 - 2.13 (m, 2H), 2.01 - 1.88 (m, 1H), 1.80 - 1.67 (m, 1H), 1.64 - 1.50 (m, 1H), 1.35 - 1.26 (m, 2H), (contains 25% methyl ester impurity); M/Z: 373, 375 [M+Na]⁺, ESI⁺, RT = 0.80 (S2). Step 20. c: Ethyl 5-[2-(4-chloro-3-fluorophenoxy)acetamido]-6-oxopiperidine-2-carboxylate

To a stirred solution of ethyl 5-amino-6-oxo-piperidine-2-carboxylate (700 mg, 3.76 mmol) and DIPEA (1.3 mL, 7.52 mmol) in DCM (8 mL) at 0° C. was added a solution of 2-(4-chloro-3-fluoro-phenoxy)acetyl chloride (838 mg, 3.76 mmol) in DCM (2 mL) and stirred at room temperature for 2 h. The mixture was diluted with DCM (20 mL) and washed with 1 M aqueous HCl (20 mL). _The organic extract was dried over _Na2SO4 , concentrated in vacuo and purified by preparative HPLC (Method 5) to give the title compound (72% purity, 433 mg, 0.836 mmol, 22% yield) as a white solid; ^1H NMR (400 MHz, chloroform-d) δ 7.41 - 7.28 (m, 2H), 6.80 - 6.74 (m, 1H), 6.73 - 6.66 (m, 1H), 6.33 - 6.25 (m, 1H), 4.51 - 4.46 (m, 2H), 4.35 - 4.22 (m, 2H), 4.20 - 4.11 (m, 1H), 2.71 - 2.49 (m, 1H), 2.47 - 2.13 (m, M/Z: 373, 375 [M+Na] ⁺ , ESI ⁺ , RT = 0.80 (S2).

Ｈ_２Ｏ（３ｍＬ）およびＭｅＯＨ（５ｍＬ）中のエチル５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－６－オキソピペリジン－２－カルボキシレート（７２％の純度、３３０ｍｇ、０．６３７ｍｍｏｌ）の溶液に、２ＭのＬｉＯＨ水溶液（０．３８ｍＬ、０．７６５ｍｍｏｌ）を滴下により添加し、混合物を室温で５時間の間撹拌した。１ＭのＨＣｌ水溶液（０．６ｍＬ）を使用して、反応混合物をｐＨ５に酸性化し、次いで、真空中で濃縮することで、標題化合物が（５５％の純度、３９７ｍｇ、０．６３３ｍｍｏｌ、９９％の収率）オフホワイトの固体として得られた；Ｍ／Ｚ：３４５、３４７、［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝０．６６、０．６８（Ｓ２）。 Intermediate 41 (Step 20.d): 5-[2-(4-chloro-3-fluorophenoxy)acetamido]-6-oxopiperidine-2-carboxylic acid

To a solution of ethyl 5-[2-(4-chloro-3-fluorophenoxy)acetamido]-6-oxopiperidine-2-carboxylate (72% purity, 330 mg, 0.637 mmol) in H ₂ O (3 mL) and MeOH (5 mL) was added 2 M aqueous LiOH (0.38 mL, 0.765 mmol) dropwise and the mixture was stirred at room temperature for 5 h. The reaction mixture was acidified to pH 5 using 1 M aqueous HCl (0.6 mL) and then concentrated in vacuo to give the title compound (55% purity, 397 mg, 0.633 mmol, 99% yield) as an off-white solid; M/Z: 345, 347, [M+H] ⁺ , ESI ⁺ , RT=0.66, 0.68 (S2).

Scheme for Route 21

ＤＣＭ（２３ｍＬ）中の１－ｔｅｒｔ－ブチル２－エチル（２Ｓ，５Ｒ）－５－［（ベンジルオキシ）アミノ］ピペリジン－１，２－ジカルボキシレート（２．３０ｇ、６．０８ｍｍｏｌ、中間体５）、ＤＭＡＰ（７４ｍｇ、０．６０８ｍｍｏｌ）およびピリジン（０．９８ｍＬ、１２．２ｍｍｏｌ）の混合物に０℃で、ベンジルカルボノクロリデート（１．３ｍＬ、９．１２ｍｍｏｌ）を添加し、混合物を室温で４時間の間撹拌した。反応混合物をブライン上に注ぎ、ＤＣＭで抽出した。合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～５０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（９１％の純度、２．９７ｇ、５．２７ｍｍｏｌ、８７％の収率）無色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) δ 7.45 - 7.27 (m, 10H), 5.28 - 5.17 (m, 2H), 4.92 - 4.84 (m, 2H), 4.56 (s, 1H), 4.28 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.51 (dd, J = 14.2, 5.0 Hz, 1H), 2.27 - 2.18 (m, 1H), 1.94 - 1.85 (m, 2H), 1.77 - 1.68 (m, 1H), 1.40 (s, 9H), 1.26 (td, J = 7.1, 3.0 Hz, 3H); M/Z: 535 [M+Na]⁺, ESI⁺, RT = 1.44 (S1). Step 21. a: 1-tert-butyl 2-ethyl (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]piperidine-1,2-dicarboxylate

To a mixture of 1-tert-butyl 2-ethyl (2S,5R)-5-[(benzyloxy)amino]piperidine-1,2-dicarboxylate (2.30 g, 6.08 mmol, intermediate 5), DMAP (74 mg, 0.608 mmol) and pyridine (0.98 mL, 12.2 mmol) in DCM (23 mL) at 0° C., benzyl carbonochloridate (1.3 mL, 9.12 mmol) was added and the mixture was stirred at room temperature for 4 h. The reaction mixture was poured onto brine and extracted with DCM. The combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-50% EtOAc in heptane) to give the title compound (91% purity, 2.97 g, 5.27 mmol, 87% yield) as a colorless oil; ¹ H NMR (400 MHz, chloroform-d) δ 7.45 - 7.27 (m, 10H), 5.28 - 5.17 (m, 2H), 4.92 - 4.84 (m, 2H), 4.56 (s, 1H), 4.28 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.51 (dd, J = 14.2, 5.0 Hz, 1H), 2.27 - 2.18 (m, 1H), 1.94 - 1.85 (m, M/Z: 535 [M+Na] ⁺ , ESI ⁺ , RT = 1.44 (S1).

ＴＨＦ（１０ｍＬ）およびＥｔＯＨ（１０ｍＬ）中の１－ｔｅｒｔ－ブチル２－エチル（２Ｓ，５Ｒ）－５－［（ベンジルオキシ）［（ベンジルオキシ）カルボニル］アミノ］ピペリジン－１，２－ジカルボキシレート（９１％の純度、２．９７ｇ、５．２７ｍｍｏｌ）の溶液に、Ｈ_２Ｏ（１０ｍＬ）中のＬｉＯＨ．Ｈ_２Ｏ（２４９ｍｇ、５．８０ｍｍｏｌ）の溶液を添加し、室温で１６時間の間撹拌した。１ＭのＨＣｌ水溶液を使用して反応混合物を約ｐＨ４に酸性化し、ＥｔＯＡｃ（２×１００ｍＬ）で抽出した。合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮し、シリカゲル（ヘプタン中２５～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（７７％の純度、２．０１ｇ、３．１９ｍｍｏｌ、６１％の収率）清澄な油状物として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 7.45 - 7.17 (m, 10H), 5.22 - 5.17 (m, 2H), 4.88 - 4.77 (m, 2H), 4.66 - 4.54 (m, 1H), 4.52 - 4.47 (m, 1H), 4.43 - 4.32 (m, 1H), 4.26 - 4.12 (m, 1H), 3.97 - 3.88 (m, 1H), 2.16 - 2.02 (m, 1H), 1.83 - 1.66 (m, 3H), 1.30 (s, 9H); M/Z: 507 [M+H]⁺, ESI⁺, RT = 1.28 (S1). Intermediate 42 (Step 21.b): (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid

To a solution of 1-tert-butyl 2-ethyl(2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]piperidine-1,2-dicarboxylate (91% purity, 2.97 g, 5.27 mmol) in THF (10 mL) and EtOH (10 mL) was added a solution of LiOH.H ₂ O (249 mg, 5.80 mmol) in H ₂ O (10 mL) and stirred at room temperature for 16 h. The reaction mixture was acidified to about pH 4 using 1 M aqueous HCl and extracted with EtOAc (2×100 mL). The combined organic extracts were dried over Na ₂ SO ₄ , concentrated in vacuo, and purified by chromatography on silica gel (25-100% EtOAc in heptane) to give the title compound (77% purity, 2.01 g, 3.19 mmol, 61% yield) as a clear oil; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.45 - 7.17 (m, 10H), 5.22 - 5.17 (m, 2H), 4.88 - 4.77 (m, 2H), 4.66 - 4.54 (m, 1H), 4.52 - 4.47 (m, 1H), 4.43 - 4.32 (m, 1H), 4.26 - 4.12 (m, 1H), 3.97 - 3.88. (m, 1H), 2.16 - 2.02 (m, 1H), 1.83 - 1.66 (m, 3H), 1.30 (s, 9H); M/Z: 507 [M+H] ⁺ , ESI ⁺ , RT = 1.28 (S1).

ＤＣＭ（２ｍＬ）中の（２Ｓ，５Ｒ）－５－［（ベンジルオキシ）［（ベンジルオキシ）カルボニル］アミノ］－１－［（ｔｅｒｔ－ブトキシ）カルボニル］ピペリジン－２－カルボン酸（７７％の純度、２００ｍｇ、０．３１８ｍｍｏｌ、中間体４２）の撹拌溶液に０℃で、１，４－ジオキサン（０．５０ｍＬ、２．０ｍｍｏｌ）中４ＭのＨＣｌを添加し、混合物を室温で２時間の間撹拌した。反応混合物を真空中で濃縮することで、標題化合物が（５８％の純度、１８０ｍｇ、０．２４８ｍｍｏｌ、７８％の収率）白色の固体として得られた；Ｍ／Ｚ：３８５［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝０．９７（Ｓ１）。 Step 21. c: (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]piperidine-2-carboxylic acid hydrochloride

To a stirred solution of (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid (77% purity, 200 mg, 0.318 mmol, intermediate 42) in DCM (2 mL) at 0° C. was added 4 M HCl in 1,4-dioxane (0.50 mL, 2.0 mmol) and the mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo to give the title compound (58% purity, 180 mg, 0.248 mmol, 78% yield) as a white solid; M/Z: 385 [M+H] ⁺ , ESI ⁺ , RT=0.97 (S1).

ＤＣＥ（５ｍＬ）中の（２Ｓ，５Ｒ）－５－［（ベンジルオキシ）［（ベンジルオキシ）カルボニル］アミノ］ピペリジン－２－カルボン酸塩酸塩（５８％の純度、１６９ｍｇ、０．２３３ｍｍｏｌ）の懸濁液に、アセトアルデヒド（３６ｍｇ、０．８０６ｍｍｏｌ）を添加し、室温で１０分間撹拌した。ＳＴＡＢ（１９８ｍｇ、０．９３ｍｍｏｌ）を添加し、混合物を室温で１６時間の間撹拌した。反応混合物を真空中で濃縮し、分取ＨＰＬＣ（方法５）によって精製することで、標題化合物が（７８ｍｇ、０．１８３ｍｍｏｌ、５９％の収率）ベージュ色の固体として得られた；Ｍ／Ｚ：４１３［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝１．００（Ｓ１）。 Step 21. d: (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-1-ethylpiperidine-2-carboxylic acid

To a suspension of (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]piperidine-2-carboxylic acid hydrochloride (58% purity, 169 mg, 0.233 mmol) in DCE (5 mL) was added acetaldehyde (36 mg, 0.806 mmol) and stirred at room temperature for 10 min. STAB (198 mg, 0.93 mmol) was added and the mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Method 5) to give the title compound (78 mg, 0.183 mmol, 59% yield) as a beige solid; M/Z: 413 [M+H] ⁺ , ESI ⁺ , RT=1.00 (S1).

ＥｔＯＨ（１０ｍＬ）中の（２Ｓ，５Ｒ）－５－［（ベンジルオキシ）［（ベンジルオキシ）カルボニル］アミノ］－１－エチルピペリジン－２－カルボン酸（７８ｍｇ、０．１８３ｍｍｏｌ）およびＢｏｃ_２Ｏ（５２ｍｇ、０．２３８ｍｍｏｌ）の溶液に、１０％のＰｄ／Ｃ（１０ｍｇ、０．０９４０ｍｍｏｌ）を添加し、混合物をＨ_２下にて室温で６時間の間撹拌した。反応混合物をセライトに通して濾過し、濾液を真空中で濃縮することで、標題化合物が（３５％の純度、１３０ｍｇ、０．１６７ｍｍｏｌ、９１％の収率）無色のガムとして得られた；Ｍ／Ｚ：２７３［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝０．７６（Ｓ１）。 Intermediate 43 (Step 21.e): (2S,5R)-5-{[(tert-butoxy)carbonyl]amino}-1-ethylpiperidine-2-carboxylic acid

To a solution of (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-1-ethylpiperidine-2-carboxylic acid (78 mg, 0.183 mmol) and Boc ₂ O (52 mg, 0.238 mmol) in EtOH (10 mL) was added 10% Pd/C (10 mg, 0.0940 mmol) and the mixture was stirred at room temperature under H ₂ for 6 h. The reaction mixture was filtered through Celite and the filtrate was concentrated in vacuo to give the title compound (35% purity, 130 mg, 0.167 mmol, 91% yield) as a colorless gum; M/Z: 273 [M+H] ⁺ , ESI ⁺ , RT=0.76 (S1).

Following general route 21, the intermediates in Table 7 were synthesized using the corresponding starting materials as exemplified by intermediate 42.

Scheme for Route 22

第１にＤＣＭ／ＭｅＯＨ（３：１）でフラッシュし、次いでＭｅＯＨ／ＤＣＭ（１：３）中２ＭのＮＨ_３で溶出するＳＣＸ－２カートリッジを使用して、エチル（２Ｓ，５Ｒ）－５－（ベンジルオキシアミノ）ピペリジン－２－カルボキシレートシュウ酸（５００ｍｇ、１．３６ｍｍｏｌ）を遊離塩基化することで、アミンが得られた。溶媒を真空中で濃縮し、残留物を無水ＤＭＦ（５ｍＬ）中に溶解させ、マイクロ波バイアルに移した。Ｋ_２ＣＯ_３（３７５ｍｇ、２．７１ｍｍｏｌ）および１－ブロモ－２－メトキシ－エタン（３８３μＬ、４．０７ｍｍｏｌ）を添加し、混合物を１２０℃で１時間の間撹拌した。反応混合物をブライン上に注ぎ、ＥｔＯＡｃ（２×５０ｍＬ）で抽出した。合わせた有機抽出物をブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ＤＣＭ中のＭｅＯＨ中０～１０％の７ＭのＮＨ_３）上のクロマトグラフィーによって精製することで、標題化合物が（９０％の純度、４２３ｍｇ、１．１３ｍｍｏｌ、８３％の収率）茶色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) δ 7.40 - 7.26 (m, 5H), 5.57 (s, 1H), 4.68 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.49 (td, J = 5.9, 1.8 Hz, 2H), 3.35 - 3.26 (m, 4H), 3.24 - 3.12 (m, 1H), 3.08 (dd, J = 8.8, 3.7 Hz, 1H), 2.83 - 2.72 (m, 1H), 2.65 - 2.55 (m, 1H), 2.18 (dd, J = 11.2, 8.2 Hz, 1H), 1.98 - 1.72 (m, 3H), 1.39 - 1.20 (m, 4H); M/Z: 337 [M+H]⁺, ESI⁺, RT = 0.86 (S1). Step 22. a: Ethyl (2S,5R)-5-[(benzyloxy)amino]-1-(2-methoxyethyl)piperidine-2-carboxylate

Ethyl (2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylate oxalate (500 mg, 1.36 mmol) was free-based using an SCX-2 cartridge, first flushed with DCM/MeOH (3:1) and then eluted with 2M NH ₃ in MeOH/DCM (1:3) to give the amine. The solvent was concentrated in vacuo and the residue was dissolved in anhydrous DMF (5 mL) and transferred to a microwave vial. K ₂ CO ₃ (375 mg, 2.71 mmol) and 1-bromo-2-methoxy-ethane (383 μL, 4.07 mmol) were added and the mixture was stirred at 120° C. for 1 h. The reaction mixture was poured onto brine and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-10% 7M _NH3 in MeOH in DCM) to give the title compound (90% purity, 423 mg, 1.13 mmol, 83% yield) as a brown oil; ^1H NMR (400 MHz, chloroform-d) δ 7.40 - 7.26 (m, 5H), 5.57 (s, 1H), 4.68 (s, 2H), 4.19 (q, J = 7.1 Hz, 2H), 3.49 (td, J = 5.9, 1.8 Hz, 2H), 3.35 - 3.26 (m, 4H), 3.24 - 3.12 (m, 1H), 3.08 (dd, J = 8.8, 3.7 Hz, 1H), 2.83 M/Z: 337 [M+H] ⁺ , ESI ⁺ , RT = 0.86 (S1).

ＥｔＯＨ（１０ｍＬ）中のエチル（２Ｓ，５Ｒ）－５－［（ベンジルオキシ）アミノ］－１－（２－メトキシエチル）ピペリジン－２－カルボキシレート（９０％の純度、４２３ｍｇ、１．１３ｍｍｏｌ）、Ｂｏｃ_２Ｏ（３２１ｍｇ、１．４７ｍｍｏｌ）および１０％のＰｄ／Ｃ（１２０ｍｇ、０．１１３ｍｍｏｌ）の溶液を、Ｈ_２下にて室温で１６時間の間撹拌した。反応混合物をセライトのパッドに通して濾過し、ＥｔＯＡｃで洗浄して、濾液を真空中で濃縮することで、標題化合物が（５０％の純度、６２７ｍｇ、０．９４９ｍｍｏｌ、８４％の収率）無色の油状物として得られた；Ｍ／Ｚ：３３１［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝０．７８（Ｓ１）。 Step 22. b: Ethyl (2S,5R)-5-{[(tert-butoxy)carbonyl]amino}-1-(2-methoxyethyl)piperidine-2-carboxylate

A solution of ethyl (2S,5R)-5-[(benzyloxy)amino]-1-(2-methoxyethyl)piperidine-2-carboxylate (90% purity, 423 mg, 1.13 mmol), Boc ₂ O (321 mg, 1.47 mmol) and 10% Pd/C (120 mg, 0.113 mmol) in EtOH (10 mL) was stirred at room temperature under H ₂ for 16 h. The reaction mixture was filtered through a pad of Celite, washed with EtOAc and the filtrate was concentrated in vacuo to give the title compound (50% purity, 627 mg, 0.949 mmol, 84% yield) as a colorless oil; M/Z: 331 [M+H] ⁺ , ESI ⁺ , RT=0.78 (S1).

ＴＨＦ（１０ｍＬ）中のエチル（２Ｓ，５Ｒ）－５－｛［（ｔｅｒｔ－ブトキシ）カルボニル］アミノ｝－１－（２－メトキシエチル）ピペリジン－２－カルボキシレート（５０％の純度、６２７ｍｇ、０．９４９ｍｍｏｌ）の溶液を、Ｈ_２Ｏ（１０ｍＬ）中のＬｉＯＨ・Ｈ_２Ｏ（４０８ｍｇ、９．４８ｍｍｏｌ）の溶液にて室温で１６時間の間処理した。１ＭのＨＣｌ Ｈ_２Ｏ水溶液（７．６ｍＬ、７．５９ｍｍｏｌ）を滴下により添加し、有機溶媒を抽出し、蒸発することで、標題化合物が（２８６ｍｇ、０．９５ｍｍｏｌ、９９％の収率）白色の固体として得られた；Ｍ／Ｚ：３０３［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝０．７９（Ｓ１）。 Intermediate 45 (Step 22.c): (2S,5R)-5-{[(tert-butoxy)carbonyl]amino}-1-(2-methoxyethyl)piperidine-2-carboxylic acid

A solution of ethyl (2S,5R)-5-{[(tert-butoxy)carbonyl]amino}-1-(2-methoxyethyl)piperidine-2-carboxylate (50% purity, 627 mg, 0.949 mmol) in THF (10 mL) was treated with a solution of LiOH.H ₂ O (408 mg, 9.48 mmol) in H ₂ O (10 mL) at room temperature for 16 h. 1M aqueous HCl H ₂ O (7.6 mL, 7.59 mmol) was added dropwise and the organic solvent was extracted and evaporated to give the title compound (286 mg, 0.95 mmol, 99% yield) as a white solid; M/Z: 303 [M+H] ⁺ , ESI ⁺ , RT=0.79 (S1).

Scheme for Route 23

無水ＤＭＦ（１０ｍＬ）中の（２Ｓ，５Ｒ）－５－［（ベンジルオキシ）［（ベンジルオキシ）カルボニル］アミノ］－１－［（ｔｅｒｔ－ブトキシ）カルボニル］ピペリジン－２－カルボン酸（７７％の純度、１．０ｇ、１．５９ｍｍｏｌ、中間体４２）の溶液に０℃で、ＨＡＴＵ（７２５ｍｇ、１．９１ｍｍｏｌ）、続いてＤＩＰＥＡ（０．５６ｍＬ、３．１８ｍｍｏｌ）を添加し、室温で１０分間撹拌した。４－クロロベンゾヒドラジド（２７１ｍｇ、１．５９ｍｍｏｌ）を次いで添加し、混合物を室温で２時間の間撹拌した。反応混合物をＨ_２Ｏ（８０ｍＬ）で希釈し、室温で２０分間撹拌し、結果として生じた懸濁液を真空下で濾過し、Ｈ_２Ｏ（５０ｍＬ）で洗浄した。残留物をシリカゲル（ヘプタン中５～８０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（９１％の純度、６４０ｍｇ、０．９１ｍｍｏｌ、５７％の収率）白色の固体として得られた；Ｍ／Ｚ：５３７、５３９［Ｍ－Ｂｏｃ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝１．３３（Ｓ１）。 Step 23. a: tert-Butyl (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-{[(4-chlorophenyl)formohydrazide]carbonyl}piperidine-1-carboxylate

To a solution of (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid (77% purity, 1.0 g, 1.59 mmol, intermediate 42) in anhydrous DMF (10 mL) at 0° C. was added HATU (725 mg, 1.91 mmol) followed by DIPEA (0.56 mL, 3.18 mmol) and stirred at room temperature for 10 min. 4-Chlorobenzohydrazide (271 mg, 1.59 mmol) was then added and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H ₂ O (80 mL), stirred at room temperature for 20 min and the resulting suspension was filtered under vacuum and washed with H ₂ O (50 mL). The residue was purified by chromatography on silica gel (5-80% EtOAc in heptane) to give the title compound (91% purity, 640 mg, 0.91 mmol, 57% yield) as a white solid; M/Z: 537, 539 [M-Boc+H] ⁺ , ESI ⁺ , RT=1.33 (S1).

ＡＣＮ（５ｍＬ）中のｔｅｒｔ－ブチル（２Ｓ，５Ｒ）－５－［（ベンジルオキシ）［（ベンジルオキシ）カルボニル］アミノ］－２－｛［（４－クロロフェニル）ホルモヒドラジド］カルボニル｝ピペリジン－１－カルボキシレート（９１％の純度、６４０ｍｇ、０．９１ｍｍｏｌ）の溶液に、ＤＩＰＥＡ（０．１２ｍＬ、０．６６９ｍｍｏｌ）およびＴｓＣｌ（１９１ｍｇ、１．０ｍｍｏｌ）を添加し、混合物を室温で４８時間の間撹拌した。１５％のＮＨ_４ＯＨ水溶液（２０ｍＬ）を添加し、混合物を室温で１５分間撹拌した。反応混合物を真空中で濃縮し、Ｈ_２Ｏ（２０ｍＬ）で希釈し、ＤＣＭ（２×３０ｍＬ）で抽出した。合わせた有機抽出物をブラインで（３０ｍＬ）洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中１０～８０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（５６０ｍｇ、０．８７７ｍｍｏｌ、９６％の収率）白色のガムとして得られた；¹H NMR (400 MHz, chloroform-d) δ 8.02 - 7.90 (m, 2H), 7.54 - 7.47 (m, 2H), 7.47 - 7.31 (m, 9H), 7.27 - 7.19 (m, 1H), 5.52 (s, 1H), 5.35 - 5.20 (m, 2H), 4.99 - 4.88 (m, 2H), 4.32 - 4.22 (m, 2H), 3.54 - 3.45 (m, 1H), 2.58 - 2.43 (m, 1H), 2.23 - 2.11 (m, 1H), 2.09 - 2.01 (m, 2H), 1.41 (s, 9H); M/Z: 641, 643 [M+Na]⁺, ESI⁺, RT = 1.53 (S1). Step 23. b: tert-Butyl (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

To a solution of tert-butyl (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-{[(4-chlorophenyl)formohydrazide]carbonyl}piperidine-1-carboxylate (91% purity, 640 mg, 0.91 mmol) in ACN (5 mL) was added DIPEA (0.12 mL, 0.669 mmol) and TsCl (191 mg, 1.0 mmol) and the mixture was stirred at room temperature for 48 h. 15% aqueous NH ₄ OH (20 mL) was added and the mixture was stirred at room temperature for 15 min. The reaction mixture was concentrated in vacuo, diluted with H ₂ O (20 mL) and extracted with DCM (2×30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (10-80% EtOAc in heptane) to give the title compound (560 mg, 0.877 mmol, 96% yield) as a white gum; ¹ H NMR (400 MHz, chloroform-d) δ 8.02 - 7.90 (m, 2H), 7.54 - 7.47 (m, 2H), 7.47 - 7.31 (m, 9H), 7.27 - 7.19 (m, 1H), 5.52 (s, 1H), 5.35 - 5.20 (m, 2H), 4.99 - 4.88 (m, 2H), 4.32 - 4.22 (m, 2H), 3.54 - 3.45 (m, 1H), 2.58 - 2.43 (m, 1H), 2.23 - 2.11 (m, 1H), 2.09 - 2.01 (m, 2H), 1.41 (s, 9H); M/Z: 641, 643 [M+Na] ⁺ , ESI ⁺ , RT = 1.53 (S1).

ＭｅＯＨ（５ｍＬ）中のｔｅｒｔ－ブチル（２Ｓ，５Ｒ）－５－［（ベンジルオキシ）［（ベンジルオキシ）カルボニル］アミノ］－２－［５－（４－クロロフェニル）－１，３，４－オキサジアゾール－２－イル］ピペリジン－１－カルボキシレート（４８０ｍｇ、０．７５２ｍｍｏｌ）の溶液に、２ＭのＬｉＯＨ水溶液（１０ｍＬ、２０．０ｍｍｏｌ）を添加し、混合物を室温で１５時間の間撹拌した。混合物を次いで５０℃に３時間の間加熱した後に、室温で１１０時間の間撹拌した。反応混合物を真空中で濃縮し、Ｈ_２Ｏ（２０ｍＬ）中に溶解させ、１ＭのＨＣｌ水溶液を使用してｐＨ９に酸性化した。溶液をＥｔＯＡｃ（２×３０ｍＬ）で抽出し、合わせた有機抽出物をブライン（３０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中１０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（９２％の純度、１９５ｍｇ、０．３７０ｍｍｏｌ、４９％の収率）得られた；¹H NMR (500 MHz, chloroform-d) δ 8.00 - 7.88 (m, 2H), 7.53 - 7.41 (m, 2H), 7.39 - 7.23 (m, 5H), 4.81 - 4.61 (m, 2H), 4.41 (d, J = 72.2 Hz, 2H), 3.14 (d, J = 65.3 Hz, 2H), 2.73 (s, 1H), 2.51 - 2.40 (m, 1H), 2.23 - 2.08 (m, 1H), 1.93 - 1.66 (m, 2H), 1.55 - 1.44 (m, 9H); M/Z: 485, 487 [M+H]⁺, ESI⁺, RT = 1.39 (S1). Step 23. c: tert-Butyl (2S,5R)-5-[(benzyloxy)amino]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

To a solution of tert-butyl (2S,5R)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (480 mg, 0.752 mmol) in MeOH (5 mL) was added 2M aqueous LiOH (10 mL, 20.0 mmol) and the mixture was stirred at room temperature for 15 h. The mixture was then heated to 50° C. for 3 h before being stirred at room temperature for 110 h. The reaction mixture was concentrated in vacuo, dissolved in H ₂ O (20 mL) and acidified to pH 9 using 1M aqueous HCl. The solution was extracted with EtOAc (2×30 mL) and the combined organic extracts were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (10-100% EtOAc in heptane) to give the title compound (92% purity, 195 mg, 0.370 mmol, 49% yield); ¹ H NMR (500 MHz, chloroform-d) δ 8.00 - 7.88 (m, 2H), 7.53 - 7.41 (m, 2H), 7.39 - 7.23 (m, 5H), 4.81 - 4.61 (m, 2H), 4.41 (d, J = 72.2 Hz, 2H), 3.14 (d, J = 65.3 Hz, 2H), 2.73 (s, 1H), 2.51 - 2.40 (m, 1H), 2.23 - 2.08 (m, 1H), 1.93 - 1.66 (m, 2H), 1.55 - 1.44 (m, 9H); M/Z: 485, 487 [M+H] ⁺ , ESI ⁺ , RT = 1.39 (S1).

ＭｅＯＨ（２０ｍＬ）中のｔｅｒｔ－ブチル（２Ｓ，５Ｒ）－５－［（ベンジルオキシ）アミノ］－２－［５－（４－クロロフェニル）－１，３，４－オキサジアゾール－２－イル］ピペリジン－１－カルボキシレート（９２％の純度、１６０ｍｇ、０．３０４ｍｍｏｌ）の溶液に－１０℃で、ＮｉＣｌ_２・６Ｈ_２Ｏ（２９１ｍｇ、１．２１ｍｍｏｌ）、続いてＮａＢＨ_４（３４４ｍｇ、９．１１ｍｍｏｌ）を添加し、混合物を室温で５時間の間撹拌した。反応混合物を真空中で濃縮し、分取ＨＰＬＣ（方法５）によって精製することで、標題化合物が（５０ｍｇ、０．１３２ｍｍｏｌ、４３％の収率）無色のガムとして得られた；Ｍ／Ｚ：３７９、３８１［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝０．９７（Ｓ１）。 Intermediate 46 (Step 23.d): tert-Butyl (2S,5R)-5-amino-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

To a solution of tert-butyl (2S,5R)-5-[(benzyloxy)amino]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (92% purity, 160 mg, 0.304 mmol) in MeOH (20 mL) at −10° C., NiCl ₂ .6H ₂ O (291 mg, 1.21 mmol) was added followed by NaBH ₄ (344 mg, 9.11 mmol) and the mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Method 5) to give the title compound (50 mg, 0.132 mmol, 43% yield) as a colorless gum; M/Z: 379, 381 [M+H] ⁺ , ESI ⁺ , RT=0.97 (S1).

Following general route 23, the intermediates in Table 8 were synthesized using the corresponding starting materials as exemplified by intermediate 46.

Scheme for Route 24

１，４－ジオキサン（７０ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－｛［（ベンジルオキシ）カルボニル］アミノ｝－２－（ヒドラジンカルボニル）ピペリジン－１－カルボキシレート（７９％の純度、１０．２ｇ、２０．５ｍｍｏｌ、中間体３０）の溶液に、Ｈ_２Ｏ（２０ｍＬ）中のＮａＨＣＯ_３（２．５８ｇ、３０．８ｍｍｏｌ）の溶液、続いてＢｒＣＮ（２．１７ｇ、２０．５ｍｍｏｌ）を添加し、混合物を室温で２．５時間の間撹拌した。反応混合物をＨ_２Ｏで希釈し、結果として生じた沈殿物を真空下で濾過し、Ｈ_２Ｏで洗浄して、標題化合物が定量的収量で（８４％の純度、１１．０２ｇ、２２．２ｍｍｏｌ）オフホワイトの粉末として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 7.51 - 7.42 (m, 1H), 7.41 - 7.27 (m, 5H), 7.05 - 6.95 (m, 2H), 5.30 (s, 1H), 5.09 - 4.97 (m, 2H), 4.11 - 3.98 (m, 1H), 2.86 - 2.76 (m, 1H), 2.29 - 2.14 (m, 1H), 1.95 - 1.79 (m, 2H), 1.65 - 1.53 (m, 1H), 1.44 - 1.30 (m, 10H); M/Z: 318 [M-Boc+H]⁺, ESI⁺, RT = 0.86 (S2). Step 24. a: tert-Butyl (2R,5S)-2-(5-amino-1,3,4-oxadiazol-2-yl)-5-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate

To a solution of tert-butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-(hydrazinecarbonyl)piperidine-1-carboxylate (79% purity, 10.2 g, 20.5 mmol, intermediate 30) in 1,4-dioxane (70 mL) was added a solution of NaHCO ₃ (2.58 g, 30.8 mmol) in H ₂ O (20 mL) followed by BrCN (2.17 g, 20.5 mmol) and the mixture was stirred at room temperature for 2.5 h. The reaction mixture was diluted with _H2O and the resulting precipitate was filtered under vacuum and washed with _H2O to give the title compound in quantitative yield (84% purity, 11.02 g, 22.2 mmol) as an off-white powder; ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.51 - 7.42 (m, 1H), 7.41 - 7.27 (m, 5H), 7.05 - 6.95 (m, 2H), 5.30 (s, 1H), 5.09 - 4.97 (m, 2H), 4.11 - 3.98 (m, 1H), 2.86 - 2.76 (m, 1H), 2.29 - 2.14 (m, 1H), 1.95 - 1.79 (m, 2H), 1.65 - 1.53 (m, 1H), 1.44 - 1.30 (m, 10H); M/Z: 318 [M-Boc+H] ⁺ , ESI ⁺ , RT = 0.86 (S2).

無水ＡＣＮ（４００ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－２－（５－アミノ－１，３，４－オキサジアゾール－２－イル）－５－｛［（ベンジルオキシ）カルボニル］アミノ｝ピペリジン－１－カルボキシレート（８４％の純度、１１．０２ｇ、２２．２ｍｍｏｌ）およびＣｕＢｒ（３当量、９．５４ｇ、６６．５ｍｍｏｌ）の溶液に、亜硝酸ｔｅｒｔ－ブチル（９０％、１７．６ｍＬ、１３３．０ｍｍｏｌ）を添加し、混合物を室温で５時間の間撹拌した。さらなる一分量のＣｕＢｒ（１．５当量、４．７７ｇ、３３．３ｍｍｏｌ）および亜硝酸ｔｅｒｔ－ブチル（９０％、８．７９ｍＬ、６６．５ｍｍｏｌ）を添加し、混合物を室温で１９時間の間撹拌した。反応混合物をＥｔＯＡｃ（２５０ｍＬ）で希釈し、ロッシェル塩（２×２００ｍＬ）およびＨ_２Ｏ（３×２００ｍＬ）で洗浄した。有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮し、シリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（２．０２ｇ、４．０３ｍｍｏｌ、１８％の収率）ベージュ色の固体として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 7.52 (d, J = 6.2 Hz, 1H), 7.41 - 7.28 (m, 5H), 5.57 - 5.41 (m, 1H), 5.05 (s, 2H), 4.08 - 3.91 (m, 1H), 3.65 - 3.53 (m, 1H), 2.96 - 2.84 (m, 1H), 2.33 - 2.23 (m, 1H), 1.99 - 1.90 (m, 1H), 1.88 - 1.72 (m, 1H), 1.65 - 1.57 (m, 1H), 1.38 (s, 9H); M/Z: 383 [M-Boc+H]⁺, ESI⁺, RT = 1.09 (S2). Step 24. b: tert-Butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-(5-bromo-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate

To a solution of tert-butyl (2R,5S)-2-(5-amino-1,3,4-oxadiazol-2-yl)-5-{[(benzyloxy)carbonyl]amino}piperidine-1-carboxylate (84% purity, 11.02 g, 22.2 mmol) and CuBr (3 eq., 9.54 g, 66.5 mmol) in anhydrous ACN (400 mL) was added tert-butyl nitrite (90%, 17.6 mL, 133.0 mmol) and the mixture was stirred at room temperature for 5 h. An additional portion of CuBr (1.5 eq., 4.77 g, 33.3 mmol) and tert-butyl nitrite (90%, 8.79 mL, 66.5 mmol) was added and the mixture was stirred at room temperature for 19 h. The reaction mixture was diluted with EtOAc (250 mL) and washed with Rochelle's salt (2×200 mL) and H ₂ O (3×200 mL). The organic extract was dried over Na ₂ SO ₄ , concentrated in vacuo, and purified by chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (2.02 g, 4.03 mmol, 18% yield) as a beige solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.52 (d, J = 6.2 Hz, 1H), 7.41 - 7.28 (m, 5H), 5.57 - 5.41 (m, 1H), 5.05 (s, 2H), 4.08 - 3.91 (m, 1H), 3.65 - 3.53 (m, 1H), 2.96 - 2.84 (m, 1H), 2.33 - 2.23 (m, 1H), 1.99 - 1.90 (m, 1H), 1.88 - 1.72 (m, 1H), 1.65 - 1.57 (m, 1H), 1.38 (s, 9H); M/Z: 383 [M-Boc+H] ⁺ , ESI ⁺ , RT = 1.09 (S2).

無水ＴＨＦ（１５ｍＬ）中の２－（トリフルオロメトキシ）エタン－１－オール（ＴＨＦ／トルエン中１３％、４．５０ｇ、４．４３ｍｍｏｌ）の溶液に０℃で、ＮａＨ（６０％、３２２ｍｇ、８．０６ｍｍｏｌ）を添加し、混合物を０℃で１０分間撹拌した。無水ＴＨＦ（１０ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－｛［（ベンジルオキシ）カルボニル］アミノ｝－２－（５－ブロモ－１，３，４－オキサジアゾール－２－イル）ピペリジン－１－カルボキシレート（２．０２ｇ、４．０３ｍｍｏｌ）を添加し、混合物を室温で２時間の間撹拌した。反応混合物をＨ_２Ｏ（５０ｍＬ）で希釈し、ＥｔＯＡｃ（３×１００ｍＬ）で抽出した。合わせた有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中で濃縮し、シリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（８５％の純度、１．６０ｇ、２．５６ｍｍｏｌ、６４％の収率）黄色の油状物として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 7.50 (d, J = 6.1 Hz, 1H), 7.43 - 7.26 (m, 5H), 5.46 - 5.29 (m, 1H), 5.04 (s, 2H), 4.80 - 4.58 (m, 2H), 4.57 - 4.41 (m, 2H), 4.43 - 4.26 (m, 1H), 3.73 - 3.51 (m, 1H), 2.96 - 2.80 (m, 1H), 2.32 - 2.16 (m, 1H), 1.96 - 1.73 (m, 2H), 1.69 - 1.49 (m, 1H), 1.37 (s, 9H); M/Z: 531 [M-Boc+H]⁺, ESI⁺, RT = 3.83 (S4). Step 24. c: tert-Butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

To a solution of 2-(trifluoromethoxy)ethan-1-ol (13% in THF/toluene, 4.50 g, 4.43 mmol) in anhydrous THF (15 mL) at 0° C. was added NaH (60%, 322 mg, 8.06 mmol) and the mixture was stirred for 10 min at 0° C. tert-Butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-(5-bromo-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (2.02 g, 4.03 mmol) in anhydrous THF (10 mL) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with H ₂ O (50 mL) and extracted with EtOAc (3×100 mL). The combined organic extracts were dried over _MgSO4 , concentrated in vacuo, and purified by chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (85% purity, 1.60 g, 2.56 mmol, 64% yield) as a yellow oil; ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.50 (d, J = 6.1 Hz, 1H), 7.43 - 7.26 (m, 5H), 5.46 - 5.29 (m, 1H), 5.04 (s, 2H), 4.80 - 4.58 (m, 2H), 4.57 - 4.41 (m, 2H), 4.43 - 4.26 (m, 1H), 3.73 - 3.51 (m, 1H), 2.96 - 2.80 (m, 1H), 2.32 - 2.16 (m, 1H), 1.96 - 1.73 (m, 2H), 1.69 - 1.49 (m, 1H), 1.37 (s, 9H); M/Z: 531 [M-Boc+H] ⁺ , ESI ⁺ , RT = 3.83 (S4).

ＥｔＯＨ（４５ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－｛［（ベンジルオキシ）カルボニル］アミノ｝－２－｛５－［２－（トリフルオロメトキシ）エトキシ］－１，３，４－オキサジアゾール－２－イル｝ピペリジン－１－カルボキシレート（８５％の純度、１．６０ｇ、２．５６ｍｍｏｌ）の溶液にＮ_２下にて、１０％のＰｄ／Ｃ（３．２７ｇ、３．０８ｍｍｏｌ）を添加し、混合物をＨ_２下にて室温で１８時間の間撹拌した。反応混合物をセライトのパッドに通して濾過し、真空中で濃縮することで、標題化合物が（４９％の純度、８４３ｍｇ、１．０４ｍｍｏｌ、４１％の収率）薄茶色の油状物として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 5.39 - 5.26 (m, 1H), 4.76 - 4.64 (m, 2H), 4.54 - 4.42 (m, 2H), 4.43 - 4.25 (m, 1H), 3.74 - 3.60 (m, 1H), 3.20 - 2.91 (m, 3H), 2.30 - 2.09 (m, 1H), 1.93 - 1.78 (m, 1H), 1.75 - 1.59 (m, 1H), 1.53 - 1.25 (m, 11H); M/Z: 397 [M+H]⁺, ESI⁺, RT = 1.76 (S4). Intermediate 48 (Step 24.d): tert-Butyl (2R,5S)-5-amino-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

To a solution of tert-butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (85% purity, 1.60 g, 2.56 mmol) in EtOH (45 mL) under _N was added 10% Pd/C (3.27 g, 3.08 mmol) and the mixture was stirred at room temperature under _H for 18 h. The reaction mixture was filtered through a pad of Celite and concentrated in vacuo to give the title compound (49% purity, 843 mg, 1.04 mmol, 41% yield) as a light brown oil; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.39 - 5.26 (m, 1H), 4.76 - 4.64 (m, 2H), 4.54 - 4.42 (m, 2H), 4.43 - 4.25 (m, 1H), 3.74 - 3.60 (m, 1H), 3.20 - 2.91 (m, 3H), 2.30 - 2.09 (m, 1H), 1.93 - 1.78 (m, 1H), 1.75 - 1.59 (m, 1H), 1.53 - 1.25 (m, 11H); M/Z: 397 [M+H] ⁺ , ESI ⁺ , RT = 1.76 (S4).

Scheme for Route 25

ＴＨＦ（２０ｍＬ）中の（１ｓ，３ｓ）－３－（トリフルオロメトキシ）シクロブタン－１－カルボン酸（５００ｍｇ、２．６３ｍｍｏｌ、中間体５４）の溶液に、ＤＩＰＥＡ（１．４ｍＬ、７．９０ｍｍｏｌ）、Ｔ３Ｐ（ＥｔＯＡｃ中５０％、４．７ｍＬ、７．９０ｍｍｏｌ）およびｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［（ベンジルオキシ）［（ベンジルオキシ）カルボニル］アミノ］－２－（ヒドラジンカルボニル）ピペリジン－１－カルボキシレート（６０％の純度、２．３０ｇ、２．７７ｍｍｏｌ、中間体２９）を添加し、混合物を室温で１８時間の間撹拌した。反応混合物をＨ_２Ｏ（５０ｍＬ）で希釈し、ＥｔＯＡｃ（２×１００ｍＬ）で抽出した。合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮し、シリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（１．６０ｇ、２．２９ｍｍｏｌ、８７％の収率）白色の固体として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 10.01 - 9.69 (m, 2H), 7.49 - 7.21 (m, 10H), 5.21 (s, 2H), 4.92 - 4.74 (m, 3H), 4.52 - 4.17 (m, 2H), 4.01 - 3.70 (m, 2H), 2.76 - 2.68 (m, 1H), 2.29 - 1.99 (m, 2H), 1.93 - 1.47 (m, 4H), 1.42 - 1.34 (m, 2H), 1.30 (s, 9H); M/Z: 687 [M+Na]⁺, ESI⁺, RT = 1.21 (S2). Step 25. a: tert-butyl (2R,5S)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-{N'-[(1s,3s)-3-(trifluoromethoxy)cyclobutanecarbonyl]hydrazinecarbonyl}piperidine-1-carboxylate

To a solution of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (500 mg, 2.63 mmol, Intermediate 54) in THF (20 mL) was added DIPEA (1.4 mL, 7.90 mmol), T3P (50% in EtOAc, 4.7 mL, 7.90 mmol) and tert-butyl (2R,5S)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-(hydrazinecarbonyl)piperidine-1-carboxylate (60% purity, 2.30 g, 2.77 mmol, Intermediate 29) and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with H ₂ O (50 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were dried over Na ₂ SO ₄ , concentrated in vacuo, and purified by chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (1.60 g, 2.29 mmol, 87% yield) as a white solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.01 - 9.69 (m, 2H), 7.49 - 7.21 (m, 10H), 5.21 (s, 2H), 4.92 - 4.74 (m, 3H), 4.52 - 4.17 (m, 2H), 4.01 - 3.70 (m, 2H), 2.76 - 2.68 (m, 1H), 2.29 - 1.99 (m, 2H), 1.93 - 1.47 (m, 4H), 1.42 - 1.34 (m, 2H), 1.30 (s, 9H); M/Z: 687 [M+Na] ⁺ , ESI ⁺ , RT = 1.21 (S2).

ＡＣＮ（１８ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［（ベンジルオキシ）［（ベンジルオキシ）カルボニル］アミノ］－２－｛Ｎ’－［（１ｓ，３ｓ）－３－（トリフルオロメトキシ）シクロブタンカルボニル］ヒドラジンカルボニル｝ピペリジン－１－カルボキシレート（１．６ｇ、２．２９ｍｍｏｌ）、Ｋ_２ＣＯ_３（２．０ｇ、１４．４ｍｍｏｌ）およびＴｓＣｌ（１．４０ｇ、７．２２ｍｍｏｌ）の懸濁液を、８０℃で１．５時間の間撹拌した。反応混合物をＥｔＯＡｃ（１００ｍＬ）とＨ_２Ｏ（５０ｍＬ）との間で分配し、有機層を単離し、ブライン（３０ｍＬ）で洗浄した。有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中で濃縮し、シリカゲル（ヘプタン中０～５０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（９２％の純度、１．０５ｇ、１．４９ｍｍｏｌ、６２％の収率）黄色の油状物として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 7.48 - 7.27 (m, 10H), 5.36 - 5.27 (m, 1H), 5.21 (s, 2H), 4.96 - 4.83 (m, 3H), 4.19 - 4.09 (m, 1H), 4.01 - 3.93 (m, 1H), 3.51 - 3.40 (m, 1H), 2.91 - 2.79 (m, 2H), 2.31 - 2.21 (m, 1H), 2.07 - 1.96 (m, 2H), 1.96 - 1.87 (m, 2H), 1.41 (s, 2H), 1.28 (d, J = 5.8 Hz, 9H); M/Z: 547 [M-Boc+H]⁺, ESI⁺, RT = 1.27 (S2). Step 25. b: tert-Butyl (2R,5S)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

A suspension of tert-butyl (2R,5S)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-{N'-[(1s,3s)-3-(trifluoromethoxy)cyclobutanecarbonyl]hydrazinecarbonyl}piperidine-1- _carboxylate (1.6 g, 2.29 mmol), _K2CO3 (2.0 g, 14.4 mmol) and TsCl (1.40 g, 7.22 mmol) in ACN (18 mL) was stirred for 1.5 h at 80° C. The reaction mixture was partitioned between EtOAc (100 mL) and _H2O (50 mL) and the organic layer was isolated and washed with brine (30 mL). The organic extract was dried over _MgSO4 , concentrated in vacuo, and purified by chromatography on silica gel (0-50% EtOAc in heptane) to give the title compound (92% purity, 1.05 g, 1.49 mmol, 62% yield) as a yellow oil; ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.48 - 7.27 (m, 10H), 5.36 - 5.27 (m, 1H), 5.21 (s, 2H), 4.96 - 4.83 (m, 3H), 4.19 - 4.09 (m, 1H), 4.01 - 3.93 (m, 1H), 3.51 - 3.40 (m, 1H), 2.91 - 2.79 (m, 2H), 2.31 - 2.21 (m, 1H), 2.07 - 1.96 (m, 2H), 1.96 - 1.87 (m, 2H), 1.41 (s, 2H), 1.28 (d, J = 5.8 Hz, 9H); M/Z: 547 [M-Boc+H] ⁺ , ESI ⁺ , RT = 1.27 (S2).

無水ＥｔＯＨ（３０ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［（ベンジルオキシ）［（ベンジルオキシ）カルボニル］アミノ］－２－｛５－［（１ｓ，３ｓ）－３－（トリフルオロメトキシ）シクロブチル］－１，３，４－オキサジアゾール－２－イル｝ピペリジン－１－カルボキシレート（０．９３ｇ、１．４３ｍｍｏｌ）の溶液に、１０％のＰｄ／Ｃ（０．１５ｇ、０．１４４ｍｍｏｌ）を添加し、結果として生じた混合物を室温でＨ_２下にて２４時間の間撹拌した。さらなる一分量の１０％のＰｄ／Ｃ（０．１５ｇ、０．１４４ｍｍｏｌ）を添加し、反応混合物を室温でＨ_２下にて２４時間の間撹拌した。さらなる一分量の１０％のＰｄ／Ｃ（０．１５ｇ、０．１４４ｍｍｏｌ）を添加し、反応混合物を室温でＨ_２下にて２４時間の間撹拌した。反応混合物を４０℃に加温し、セライトのパッドを介して濾過し、ＥｔＯＨで十分に洗浄した。濾液を真空中で濃縮し、シリカゲル（ＤＣＭ中０～２０％のＭｅＯＨ）上のクロマトグラフィーによって精製することで、標題化合物が（３２１ｍｇ、０．７７４ｍｍｏｌ、５４％の収率）淡黄色の油状物として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 5.39 (s, 1H), 4.90 (p, J = 7.5 Hz, 1H), 3.69 (d, J = 13.1 Hz, 1H), 3.52 - 3.36 (m, 2H), 3.06 - 2.92 (m, 2H), 2.92 - 2.76 (m, 2H), 2.32 - 2.13 (m, 2H), 1.96 - 1.85 (m, 1H), 1.80 - 1.59 (m, 1H), 1.49 (d, J = 13.6 Hz, 1H), 1.41 (s, 9H); M/Z: 407 [M+H]⁺, ESI⁺, RT = 0.71 - 0.76 (S2). Intermediate 49 (Step 25.c): tert-Butyl (2R,5S)-5-amino-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

To a solution of tert-butyl (2R,5S)-5-[(benzyloxy)[(benzyloxy)carbonyl]amino]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (0.93 g, 1.43 mmol) in absolute EtOH (30 mL) was added 10% Pd/C (0.15 g, 0.144 mmol) and the resulting mixture was stirred at room temperature under _H2 for 24 h. An additional portion of 10% Pd/C (0.15 g, 0.144 mmol) was added and the reaction mixture was stirred at room temperature under _H2 for 24 h. An additional portion of 10% Pd/C (0.15 g, 0.144 mmol) was added and the reaction mixture was stirred at room temperature under _H2 for 24 h. The reaction mixture was warmed to 40° C. and filtered through a pad of Celite, washing thoroughly with EtOH. The filtrate was concentrated in vacuo and purified by chromatography on silica gel (0-20% MeOH in DCM) to give the title compound (321 mg, 0.774 mmol, 54% yield) as a pale yellow oil; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 5.39 (s, 1H), 4.90 (p, J = 7.5 Hz, 1H), 3.69 (d, J = 13.1 Hz, 1H), 3.52 - 3.36 (m, 2H), 3.06 - 2.92 (m, 2H), 2.92 - 2.76 (m, 2H), 2.32 - 2.13 (m, 2H), 1.96 - 1.85 (m, 1H), 1.80 - 1.59 (m, 1H), 1.49 (d, J = 13.6 Hz, 1H), 1.41 (s, 9H); M/Z: 407 [M+H] ⁺ , ESI ⁺ , RT = 0.71 - 0.76 (S2).

Scheme for Route 26

４つの圧力管に分けられたｔｅｒｔ－ブチル３－ヒドロキシアゼチジン－１－カルボキシレート（５．０ｇ、２８．９ｍｍｏｌ）、１－（エテニルオキシ）ブタン（５６ｍＬ、０．４３３ｍｏｌ）、バソフェナントロリン（４８０ｍｇ、１．４４ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（９８１ｍｇ、１．４４ｍｍｏｌ）およびＥｔ_３Ｎ（１．７ｍＬ、１２．１ｍｍｏｌ）の混合物を、５分間Ｎ_２を使用して脱ガスした後に、密閉し、８０℃で２４時間の間加熱した。反応混合物を室温に冷却し、セライトのパッドを介して濾過し、ＥｔＯＡｃで洗浄した。濾液を真空中で濃縮し、シリカゲル（ヘプタン中０～２５％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（９３％の純度、３．６０ｇ、１６．８ｍｍｏｌ、５８％の収率）黄色の油状物として得られた；¹H NMR (500 MHz, chloroform-d) δ 6.37 (dd, J = 14.5, 6.9 Hz, 1H), 4.58 (tt, J = 6.5, 4.2 Hz, 1H), 4.17 (ddd, J = 9.7, 6.5, 1.0 Hz, 2H), 4.08 (dd, J = 6.9, 2.5 Hz, 1H), 3.96 (dd, J = 14.5, 2.5 Hz, 1H), 3.90 (ddd, J = 9.8, 4.2, 0.9 Hz, 2H), 1.44 (s, 9H); M/Z: no mas ion observed [M+H]⁺, ESI⁺, RT = 0.94 (S2). Step 26. a: tert-Butyl 3-(ethenyloxy)azetidine-1-carboxylate

A mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (5.0 g, 28.9 mmol), 1-(ethenyloxy)butane (56 mL, 0.433 mol), bathophenanthroline (480 mg, 1.44 mmol), Pd(OAc) ₂ (981 mg, 1.44 mmol) and Et ₃ N (1.7 mL, 12.1 mmol) separated into four pressure tubes was degassed using N ₂ for 5 min before being sealed and heated at 80° C. for 24 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite, washing with EtOAc. The filtrate was concentrated in vacuo and purified by chromatography on silica gel (0-25% EtOAc in heptane) to give the title compound (93% purity, 3.60 g, 16.8 mmol, 58% yield) as a yellow oil; ¹ H NMR (500 MHz, chloroform-d) δ 6.37 (dd, J = 14.5, 6.9 Hz, 1H), 4.58 (tt, J = 6.5, 4.2 Hz, 1H), 4.17 (ddd, J = 9.7, 6.5, 1.0 Hz, 2H), 4.08 (dd, J = 6.9, 2.5 Hz, 1H), 3.96 (dd, J = 14.5, 2.5 Hz, 1H), 3.90 (ddd, J = 9.8, 4.2, 0.9 Hz, 2H), 1.44 (s, 9H); M/Z: no mas ion observed [M+H] ⁺ , ESI ⁺ , RT = 0.94 (S2).

ＤＣＥ（１４ｍＬ）中のｔｅｒｔ－ブチル３－（エテニルオキシ）アゼチジン－１－カルボキシレート（９３％の純度、３．６０ｇ、１６．８ｍｍｏｌ）およびクロロ（ヨード）メタン（９．４８ｇ、５３．８ｍｍｏｌ）の溶液に－５℃で、ヘキサン（３０ｍＬ、２６．９ｍｍｏｌ）中の０．９Ｍジエチル亜鉛の溶液を滴下により６０分かけて、内部温度を０℃から－５℃の間に維持しながら添加した。混合物を室温に加温し、３０分間撹拌した。反応混合物を０℃に冷却し、飽和ＮＨ_４Ｃｌ水溶液（５ｍＬ）、続いてＮＨ_４ＯＨ溶液（５ｍＬ）を使用してクエンチした。溶液をメチルｔｅｒｔ－ブチルエーテル（３×２０ｍＬ）で抽出し、合わせた有機抽出物をブライン（２５ｍＬ）で洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～２５％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（１．０５ｇ、４．９２ｍｍｏｌ、２９％の収率）無色の油状物として得られた；¹H NMR (500 MHz, chloroform-d) δ 4.25 (tt, J = 6.6, 4.5 Hz, 1H), 4.02 (ddd, J = 9.4, 6.6, 0.9 Hz, 2H), 3.82 - 3.72 (m, 2H), 3.17 (tt, J = 6.1, 3.0 Hz, 1H), 1.36 (s, 9H), 0.53 (dq, J = 5.0, 3.4, 2.6 Hz, 2H), 0.45 - 0.37 (m, 2H). Step 26. b: tert-Butyl 3-cyclopropoxyazetidine-1-carboxylate

To a solution of tert-butyl 3-(ethenyloxy)azetidine-1-carboxylate (93% purity, 3.60 g, 16.8 mmol) and chloro(iodo)methane (9.48 g, 53.8 mmol) in DCE (14 mL) at −5° C. was added a solution of 0.9 M diethylzinc in hexanes (30 mL, 26.9 mmol) dropwise over 60 min while maintaining the internal temperature between 0° C. and −5° C. The mixture was allowed to warm to room temperature and stirred for 30 min. The reaction mixture was cooled to 0° C. and quenched using saturated aqueous NH ₄ Cl solution (5 mL) followed by NH ₄ OH solution (5 mL). The solution was extracted with methyl tert-butyl ether (3×20 mL) and the combined organic extracts were washed with brine (25 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-25% EtOAc in heptane) to give the title compound (1.05 g, 4.92 mmol, 29% yield) as a colorless oil; ¹ H NMR (500 MHz, chloroform-d) δ 4.25 (tt, J = 6.6, 4.5 Hz, 1H), 4.02 (ddd, J = 9.4, 6.6, 0.9 Hz, 2H), 3.82 - 3.72 (m, 2H), 3.17 (tt, J = 6.1, 3.0 Hz, 1H), 1.36 (s, 9H), 0.53 (dq, J = 5.0, 3.4, 2.6 Hz, 2H), 0.45 - 0.37 (m, 2H).

ＴＨＦ（３ｍＬ）中のｔｅｒｔ－ブチル３－シクロプロポキシアゼチジン－１－カルボキシレート（１．０５ｇ、４．９２ｍｍｏｌ）の溶液に０℃で、１，４－ジオキサン（４．９ｍＬ、１９．７ｍｍｏｌ）中４ＭのＨＣｌを滴下により添加し、混合物を室温で３時間の間撹拌した。反応混合物を真空中で濃縮し、２－プロパノールを使用して共沸することで、標題化合物が（７５％の純度、０．７５ｇ、３．７３ｍｍｏｌ、７６％の収率）ベージュ色の粉末として得られた；¹H NMR (500 MHz, methanol-d₄) δ 4.62 - 4.52 (m, 1H), 4.35 - 4.27 (m, 2H), 4.04 - 3.97 (m, 2H), 3.40 (tt, J = 6.0, 3.0 Hz, 1H), 0.64 - 0.59 (m, 2H), 0.56 - 0.50 (m, 2H). Intermediate 50 (Step 26.c): 3-Cyclopropoxyazetidine hydrochloride

To a solution of tert-butyl 3-cyclopropoxyazetidine-1-carboxylate (1.05 g, 4.92 mmol) in THF (3 mL) at 0° C. was added dropwise 4 M HCl in 1,4-dioxane (4.9 mL, 19.7 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo and azeotroped with 2-propanol to give the title compound (75% purity, 0.75 g, 3.73 mmol, 76% yield) as a beige powder; ¹ H NMR (500 MHz, methanol-d ₄ ) δ 4.62 - 4.52 (m, 1H), 4.35 - 4.27 (m, 2H), 4.04 - 3.97 (m, 2H), 3.40 (tt, J = 6.0, 3.0 Hz, 1H), 0.64 - 0.59 (m, 2H), 0.56 - 0.50 (m, 2H).

Scheme for Route 27

ベンジル３－ヒドロキシシクロブタン－１－カルボキシレート（５．０ｇ、２４．２ｍｍｏｌ）、１－（エテニルオキシ）ブタン（４７ｍＬ、０．３６４ｍｏｌ）、バソフェナントロリン（４０３ｍｇ、１．２１ｍｍｏｌ）、Ｐｄ（ＯＡｃ）_２（８２４ｍｇ、１．２１ｍｍｏｌ）およびＥｔ_３Ｎ（１．４ｍＬ、１０．２ｍｍｏｌ）の混合物を、Ｎ_２下にて８０℃で２４時間の間撹拌した。反応混合物を室温に冷却し、セライトを介して濾過し、ＥｔＯＡｃ（１００ｍＬ）で洗浄した。濾液を真空中で濃縮し、結果として生じた残留物をシリカゲル（ヘプタン中０～５０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（８０％の純度、４．６４ｇ、１６．０ｍｍｏｌ、６６％の収率）黄色の油状物として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 7.47 - 7.27 (m, 5H), 6.37 (dd, J = 14.4, 6.9 Hz, 1H), 5.12 (s, 2H), 4.40 - 4.27 (m, 1H), 4.12 (dd, J = 14.4, 1.8 Hz, 1H), 4.00 (dd, J = 6.8, 1.8 Hz, 1H), 2.92 - 2.79 (m, 1H), 2.67 - 2.56 (m, 2H), 2.17 - 2.04 (m, 2H); M/Z: 233 [M+H]⁺, ESI⁺, RT = 1.01 (S2). Step 27. a: Benzyl 3-(ethenyloxy)cyclobutane-1-carboxylate

A mixture of benzyl 3-hydroxycyclobutane-1-carboxylate (5.0 g, 24.2 mmol), 1-(ethenyloxy)butane (47 mL, 0.364 mol), bathophenanthroline (403 mg, 1.21 mmol), Pd(OAc) ₂ (824 mg, 1.21 mmol) and Et ₃ N (1.4 mL, 10.2 mmol) was stirred at 80° C. under N ₂ for 24 h. The reaction mixture was cooled to room temperature and filtered through Celite, washing with EtOAc (100 mL). The filtrate was concentrated in vacuo and the resulting residue was purified by chromatography on silica gel (0-50% EtOAc in heptane) to give the title compound (80% purity, 4.64 g, 16.0 mmol, 66% yield) as a yellow oil; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.47 - 7.27 (m, 5H), 6.37 (dd, J = 14.4, 6.9 Hz, 1H), 5.12 (s, 2H), 4.40 - 4.27 (m, 1H), 4.12 (dd, J = 14.4, 1.8 Hz, 1H), 4.00 (dd, J = 6.8, 1.8 Hz, 1H), 2.92 - 2.79 (m, 1H), 2.67 - 2.56 (m, 2H), 2.17 - 2.04 (m, 2H); M/Z: 233 [M+H] ⁺ , ESI ⁺ , RT = 1.01 (S2).

ＤＣＥ（４０ｍＬ）中のベンジル３－（エテニルオキシ）シクロブタン－１－カルボキシレート（８０％の純度、４．６４ｇ、１６．０ｍｍｏｌ）の溶液に０℃で、クロロ（ヨード）メタン（３．７ｍＬ、５１．１ｍｍｏｌ）、続いてヘキサン（２８ｍＬ、２５．６ｍｍｏｌ）中０．９ＭのＺｎＥｔ_２を滴下により添加し、混合物を室温で２時間の間撹拌した。反応混合物を０℃に冷却し、飽和ＮＨ_４Ｃｌ水溶液（３０ｍＬ）、続いてＮＨ_４ＯＨ溶液（３０ｍＬ）を使用してクエンチした。該水溶液をＥｔＯＡｃ（３×１００ｍＬ）で抽出し、合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～５０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（９０％の純度、１．５５ｇ、５．６６ｍｍｏｌ、３５％の収率）無色の油状物として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 7.40 - 7.31 (m, 5H), 5.09 (s, 2H), 4.00 - 3.91 (m, 1H), 3.23 - 3.16 (m, 1H), 2.82 - 2.71 (m, 1H), 2.48 - 2.44 (m, 2H), 2.08 - 1.94 (m, 2H), 0.48 - 0.40 (m, 2H), 0.43 - 0.35 (m, 2H); M/Z: 247 [M+H]⁺, ESI⁺, RT = 1.00 (S2). Step 27.b: Benzyl 3-cyclopropoxycyclobutane-1-carboxylate

To a solution of benzyl 3-(ethenyloxy)cyclobutane-1-carboxylate (80% purity, 4.64 g, 16.0 mmol) in DCE (40 mL) at 0° C. was added dropwise chloro(iodo)methane (3.7 mL, 51.1 mmol), followed by 0.9 M ZnEt ₂ in hexanes (28 mL, 25.6 mmol), and the mixture was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and quenched using saturated aqueous NH ₄ Cl solution (30 mL), followed by NH ₄ OH solution (30 mL). The aqueous solution was extracted with EtOAc (3×100 mL), and the combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-50% EtOAc in heptane) to give the title compound (90% purity, 1.55 g, 5.66 mmol, 35% yield) as a colorless oil; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.40 - 7.31 (m, 5H), 5.09 (s, 2H), 4.00 - 3.91 (m, 1H), 3.23 - 3.16 (m, 1H), 2.82 - 2.71 (m, 1H), 2.48 - 2.44 (m, 2H), 2.08 - 1.94 (m, 2H), 0.48 - 0.40 (m, 2H), 0.43 - 0.35 (m, 2H); M/Z: 247 [M+H] ⁺ , ESI ⁺ , RT = 1.00 (S2).

無水ＥｔＯＨ（２０ｍＬ）中のベンジル３－シクロプロポキシシクロブタン－１－カルボキシレート（９０％の純度、１．５５ｇ、５．６６ｍｍｏｌ）の溶液に、１０％のＰｄ／Ｃ（６０６ｍｇ、０．５７０ｍｍｏｌ）を添加し、混合物を室温でＨ_２下にて２４時間の間撹拌した。反応混合物をセライト上で濾過し、ＥｔＯＡｃ（５０ｍＬ）で洗浄して、濾液を真空中で濃縮することで、標題化合物が（９０％の純度、９８１ｍｇ、５．６５ｍｍｏｌ）定量的収量で無色の油状物として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 11.88 (s, 1H), 4.14 - 3.97 (m, 1H), 3.97 - 3.88 (m, 1H), 3.21 - 3.17 (m, 1H), 2.43 - 2.38 (m, 2H), 1.99 - 1.88 (m, 2H), 0.48 - 0.35 (m, 4H); M/Z: 157 [M+H]⁺, ESI⁺, RT = 0.64 (S2). Intermediate 51 (Step 27.c): 3-Cyclopropoxycyclobutane-1-carboxylic acid

To a solution of benzyl 3-cyclopropoxycyclobutane-1-carboxylate (90% purity, 1.55 g, 5.66 mmol) in absolute EtOH (20 mL) was added 10% Pd/C (606 mg, 0.570 mmol) and the mixture was stirred at room temperature under _H for 24 h. The reaction mixture was filtered over Celite, washed with EtOAc (50 mL) and the filtrate was concentrated in vacuo to give the title compound (90% purity, 981 mg, 5.65 mmol) in quantitative yield as a colorless oil; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 11.88 (s, 1H), 4.14 - 3.97 (m, 1H), 3.97 - 3.88 (m, 1H), 3.21 - 3.17 (m, 1H), 2.43 - 2.38 (m, 2H), 1.99 - 1.88 (m, 2H), 0.48 - 0.35 (m, 4H); M/Z: 157 [M+H] ⁺ , ESI ⁺ , RT = 0.64 (S2).

Scheme for Route 28

無水ＴＨＦ（１５ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－（ヒドラジンカルボニル）ピペリジン－１－カルボキシレート（３００ｍｇ、０．６７４ｍｍｏｌ、中間体２６）の溶液に、ＴＣＤＩ（１４４ｍｇ、０．８０９ｍｍｏｌ）を添加し、混合物を７０℃で１２時間の間撹拌した。反応混合物を室温に冷却し、Ｈ_２Ｏ（２０ｍＬ）で希釈し、ＥｔＯＡｃ（２×３０ｍＬ）で抽出した。合わせた有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（８５％の純度、３６０ｍｇ、０．６２８ｍｍｏｌ、９３％の収率）ベージュ色の粉末として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 8.06 (d, J = 6.9 Hz, 1H), 7.98 (s, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.18 (s, 2H), 7.05 (dd, J = 11.4, 2.8 Hz, 1H), 6.83 (dd, J = 9.0, 2.0 Hz, 1H), 5.31 (s, 1H), 3.89 (s, 2H), 2.97 (d, J = 12.0 Hz, 1H), 2.15 (dd, J = 11.6, 6.6 Hz, 1H), 1.94 (d, J = 13.9 Hz, 1H), 1.78 (t, J = 13.5 Hz, 1H), 1.62 (d, J = 12.4 Hz, 1H), 1.39 (s, 9H); M/Z: 485, 487 [M-H]^-, ESI^-, RT = 0.98 (S2). Step 28. a: tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(5-sulfanyl-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate

To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(hydrazinecarbonyl)piperidine-1-carboxylate (300 mg, 0.674 mmol, Intermediate 26) in anhydrous THF (15 mL) was added TCDI (144 mg, 0.809 mmol) and the mixture was stirred for 12 h at 70° C. The reaction mixture was cooled to room temperature, diluted with H ₂ O (20 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over _MgSO4 and concentrated in vacuo to give the title compound (85% purity, 360 mg, 0.628 mmol, 93% yield) as a beige powder; ^1H NMR (500 MHz, DMSO- _d6 ) δ 8.06 (d, J = 6.9 Hz, 1H), 7.98 (s, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.18 (s, 2H), 7.05 (dd, J = 11.4, 2.8 Hz, 1H), 6.83 (dd, J = 9.0, 2.0 Hz, 1H), 5.31 (s, 1H), 3.89 (s, 2H), 2.97 (d, J = 12.0 Hz, 1H), 2.15 (dd, J = 11.6, 6.6 Hz, 1H), 1.94 (d, J = 13.9 Hz, 1H), 1.78 (t, J = 13.5 Hz, 1H), 1.62 (d, J = 12.4Hz, 1H), 1.39 (s, 9H); 487 [MH] ^- , ESI ^- , RT = 0.98 (S2).

ＭｅＩ（０．４３ｍＬ、６．９８ｍｍｏｌ）を、ｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－（５－スルファニル－１，３，４－オキサジアゾール－２－イル）ピペリジン－１－カルボキシレート（８５％の純度、２．０ｇ、３．４９ｍｍｏｌ）、Ｋ_２ＣＯ_３（９６５ｍｇ、６．９８ｍｍｏｌ）およびＤＭＦ（１５ｍＬ）の懸濁液に滴下により添加し、混合物を室温で３時間の間撹拌した。反応混合物を１ＭのＮａＯＨ水溶液（１０ｍＬ）で希釈し、ＤＣＭ（２×３０ｍＬ）で抽出した。合わせた有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（１．８０ｇ、３．４１ｍｍｏｌ、９８％の収率）白色の固体として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (d, J = 7.0 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.05 (dd, J = 11.4, 2.9 Hz, 1H), 6.90 - 6.72 (m, 1H), 5.48 (s, 1H), 4.69 - 4.52 (m, 2H), 3.91 (d, J = 12.7 Hz, 2H), 2.97 (d, J = 12.4 Hz, 1H), 2.70 (s, 3H), 2.33 - 2.16 (m, 1H), 2.02 (d, J = 19.2 Hz, 1H), 1.88 - 1.69 (m, 1H), 1.65 (d, J = 13.0 Hz, 1H), 1.39 (s, 9H); M/Z: 401, 403 [M-Boc+H]⁺, ESI⁺, RT = 1.02 (S2). Step 28. b: tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(methylsulfanyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

MeI (0.43 mL, 6.98 mmol) was added dropwise to a suspension of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(5-sulfanyl-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (85% purity, 2.0 g, 3.49 mmol), K ₂ CO ₃ (965 mg, 6.98 mmol) and DMF (15 mL) and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with 1 M aqueous NaOH (10 mL) and extracted with DCM (2×30 mL). The combined organic extracts were dried over _MgSO4 and concentrated in vacuo to give the title compound (1.80 g, 3.41 mmol, 98% yield) as a white solid; ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.11 (d, J = 7.0 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.05 (dd, J = 11.4, 2.9 Hz, 1H), 6.90 - 6.72 (m, 1H), 5.48 (s, 1H), 4.69 - 4.52 (m, 2H), 3.91 (d, J = 12.7 Hz, 2H), 2.97 (d, J = 12.4 Hz, 1H), 2.70 (s, 3H), 2.33 - 2.16 (m, 1H), 2.02 (d, J = 19.2 Hz, 1H), 1.88 - 1.69 (m, 1H), 1.65 (d, J = 13.0 Hz, 1H), 1.39 (s, 9H); M/Z: 401, 403 [M-Boc+H] ⁺ , ESI ⁺ , RT = 1.02 (S2).

ＤＣＭ（４０ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－［５－（メチルスルファニル）－１，３，４－オキサジアゾール－２－イル］ピペリジン－１－カルボキシレート（１．８０ｇ、３．４１ｍｍｏｌ）およびｍ－ＣＰＢＡ（６０％の純度、２．９５ｇ、１０．２ｍｍｏｌ）の溶液を、室温で４８時間の間撹拌した。反応混合物をＤＣＭ（２０ｍＬ）および飽和Ｎａ_２ＳＯ_３溶液で希釈し、室温で１５分間撹拌した。相分離器を使用して有機層を単離し、次いで、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～４０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（８９％の純度、１．０７ｇ、１．７９ｍｍｏｌ、５２％の収率）薄茶色の固体として得られた；Ｍ／Ｚ：４３３、４３５［Ｍ－Ｂｏｃ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝０．９９（Ｓ２）。 Intermediate 52 (Step 28.c): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(5-methanesulfonyl-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate

A solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(methylsulfanyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (1.80 g, 3.41 mmol) and m-CPBA (60% purity, 2.95 g, 10.2 mmol) in DCM (40 mL) was stirred at room temperature for 48 h. The reaction mixture was diluted with DCM (20 mL) and saturated Na ₂ SO ₃ solution and stirred at room temperature for 15 min. The organic layer was isolated using a phase separator and then concentrated in vacuo. The residue was purified by chromatography on silica gel (0-40% EtOAc in heptane) to give the title compound (89% purity, 1.07 g, 1.79 mmol, 52% yield) as a light brown solid; M/Z: 433, 435 [M-Boc+H] ⁺ , ESI ⁺ , RT=0.99 (S2).

Scheme for Route 29

無水ＤＭＦ（２０ｍＬ）中の（２Ｒ，５Ｓ）－５－｛［（ベンジルオキシ）カルボニル］アミノ｝－１－［（ｔｅｒｔ－ブトキシ）カルボニル］ピペリジン－２－カルボン酸（９４％の純度、２．２１ｇ、５．９３ｍｍｏｌ、中間体４）、ＤＩＰＥＡ（２．１ｍＬ、１１．９ｍｍｏｌ）および４－クロロベンゾヒドラジド（１．１１ｇ、６．５２ｍｍｏｌ）の溶液に、ＨＡＴＵ（２．７１ｇ、７．１１ｍｍｏｌ）を添加し、混合物を室温で２０時間の間撹拌した。反応混合物を飽和ＮａＨＣＯ_３水溶液（２０ｍＬ）で希釈し、ＥｔＯＡｃ（２×５０ｍＬ）で抽出した。合わせた有機抽出物をブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（７６％の純度、１．６１ｇ、２．４３ｍｍｏｌ、４１％の収率）黄色の油状物として得られた；Ｍ／Ｚ：４０３、４０５［Ｍ－Ｂｏｃ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝０．９８（Ｓ２）。 Step 29. a: tert-Butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-[N'-(4-chlorobenzoyl)hydrazinecarbonyl]piperidine-1-carboxylate

To a solution of (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-1-[(tert-butoxy)carbonyl]piperidine-2-carboxylic acid (94% purity, 2.21 g, 5.93 mmol, intermediate 4), DIPEA (2.1 mL, 11.9 mmol) and 4-chlorobenzohydrazide (1.11 g, 6.52 mmol) in anhydrous DMF (20 mL) was added HATU (2.71 g, 7.11 mmol) and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with saturated aqueous NaHCO ₃ (20 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (76% purity, 1.61 g, 2.43 mmol, 41% yield) as a yellow oil; M/Z: 403, 405 [M-Boc+H] ⁺ , ESI ⁺ , RT=0.98 (S2).

ＡＣＮ（１２ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－｛［（ベンジルオキシ）カルボニル］アミノ｝－２－［Ｎ’－（４－クロロベンゾイル）ヒドラジンカルボニル］ピペリジン－１－カルボキシレート（７６％、１．６１ｇ、２．４３ｍｍｏｌ）、Ｋ_２ＣＯ_３（２．０２ｇ、１４．６ｍｍｏｌ）およびＴｓＣｌ（１．３９ｇ、７．３０ｍｍｏｌ）の混合物を、８０℃で１．５時間の間で撹拌した。反応混合物を室温に冷却し、Ｈ_２Ｏ（１０ｍＬ）およびブライン（１０ｍＬ）で希釈し、ＥｔＯＡｃ（２×３０ｍＬ）で抽出した。合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮し、シリカゲル（ヘプタン中０～５０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（８５％の純度、４１０ｍｇ、０．７１９ｍｍｏｌ、３０％の収率）ベージュのガムとして得られた；Ｍ／Ｚ：４８５、４８７［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝１．７１（Ｓ１）。 Step 29. b: tert-Butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

A mixture of tert-butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-[N'-(4- _{chlorobenzoyl} )hydrazinecarbonyl]piperidine-1-carboxylate (76%, 1.61 g, 2.43 mmol), _K2CO3 (2.02 g, 14.6 mmol) and TsCl (1.39 g, 7.30 mmol) in ACN (12 mL) was stirred for 1.5 h at 80° C. The reaction mixture was cooled to room temperature, diluted with _H2O (10 mL) and brine (10 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were dried over Na ₂ SO ₄ , concentrated in vacuo, and purified by chromatography on silica gel (0-50% EtOAc in heptane) to give the title compound (85% purity, 410 mg, 0.719 mmol, 30% yield) as a beige gum; M/Z: 485, 487 [M+H] ⁺ , ESI ⁺ , RT=1.71 (S1).

ＭｅＯＨ（４０ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－｛［（ベンジルオキシ）カルボニル］アミノ｝－２－［５－（４－クロロフェニル）－１，３，４－オキサジアゾール－２－イル］ピペリジン－１－カルボキシレート（４１０ｍｇ、０．８４５ｍｍｏｌ）の溶液に０℃で、ＮｉＣｌ_２・Ｈ_２Ｏ（８１１ｍｇ、３．３８ｍｍｏｌ）、続いてＮａＢＨ_４（９５９ｍｇ、２５．３６ｍｍｏｌ）を添加し、混合物を室温で１８時間の間撹拌した。反応混合物を真空中で濃縮し、Ｈ_２ＯおよびＥｔＯＡｃ中に溶解させ、結果として生じた懸濁液をセライトに通して濾過した。相を分離させ、水性層をＥｔＯＡｃでさらに抽出した。合わせた有機抽出物をブラインで洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物を分取ＨＰＬＣ（方法７）によって精製することで、標題化合物が（１４２ｍｇ、０．３７５ｍｍｏｌ、４４％の収率）得られた；¹H NMR (500 MHz, chloroform-d) δ 8.40 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 5.65 (s, 1H), 4.31 (d, J = 13.4 Hz, 1H), 3.61 (s, 1H), 3.24 (s, 1H), 2.45 (s, 1H), 2.25 (d, J = 13.3 Hz, 1H), 2.08 (s, 2H), 1.45 (s, 9H); M/Z: 379, 381 [M+H]⁺, ESI⁺, RT = 0.73 (S2). Intermediate 53 (Step 29.c): tert-Butyl (2R,5S)-5-amino-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

To a solution of tert-butyl (2R,5S)-5-{[(benzyloxy)carbonyl]amino}-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (410 mg, 0.845 mmol) in MeOH (40 mL) at 0° C. was added NiCl ₂ H ₂ O (811 mg, 3.38 mmol) followed by NaBH ₄ (959 mg, 25.36 mmol) and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, dissolved in H ₂ O and EtOAc and the resulting suspension was filtered through Celite. The phases were separated and the aqueous layer was further extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative HPLC (Method 7) to give the title compound (142 mg, 0.375 mmol, 44% yield); ¹ H NMR (500 MHz, chloroform-d) δ 8.40 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 5.65 (s, 1H), 4.31 (d, J = 13.4 Hz, 1H), 3.61 (s, 1H), 3.24 (s, 1H), 2.45 (s, 1H), 2.25 (d, J = 13.3 Hz, 1H), 2.08 (s, 2H), 1.45 (s, 9H); M/Z: 379, 381 [M+H] ⁺ , ESI ⁺ , RT = 0.73 (S2).

Scheme for Route 30

２－フルオロピリジン（１５ｍＬ、０．１８０ｍｏｌ）およびＴＭＳ－ＣＦ_３（２７ｍＬ、０．１８０ｍｏｌ）を順次に、ＥｔＯＡｃ（５００ｍＬ）中のベンジル（１ｓ，３ｓ）－３－ヒドロキシシクロブタン－１－カルボキシレート（１２．４ｇ、５９．９ｍｍｏｌ）、ＡｇＯＴｆ（４６．３ｇ、０．１８０ｍｏｌ）、セレクトフルオル（３１．８ｇ、８９．８ｍｍｏｌ）およびＫＦ（１３．９ｇ、０．２４０ｍｏｌ）の溶液に滴下により添加し、混合物を室温でＮ_２下にて２０時間の間、箔で覆われたフラスコの中で撹拌した。反応混合物をセライトに通して濾過し、ＥｔＯＡｃ（１００ｍＬ）で洗浄して、真空中で濃縮した。残留物をシリカゲル（ヘプタン中５～３０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（７．４７ｇ、２７．２ｍｍｏｌ、４５％の収率）無色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) δ 7.43 - 7.29 (m, 5H), 5.14 (s, 2H), 4.57 (p, J = 7.5 Hz, 1H), 2.82 - 2.69 (m, 1H), 2.64 (dtd, J = 10.0, 7.3, 2.6 Hz, 2H), 2.53 (qd, J = 9.8, 9.4, 2.0 Hz, 2H); ¹⁹F NMR (376 MHz, chloroform-d) δ -59.56. Step 30. a: Benzyl (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylate

2-Fluoropyridine (15 mL, 0.180 mol) and TMS-CF ₃ (27 mL, 0.180 mol) were added dropwise successively to a solution of benzyl (1s,3s)-3-hydroxycyclobutane-1-carboxylate (12.4 g, 59.9 mmol), AgOTf (46.3 g, 0.180 mol), Selectfluor (31.8 g, 89.8 mmol) and KF (13.9 g, 0.240 mol) in EtOAc (500 mL) and the mixture was stirred in a foil-covered flask at room temperature under N ₂ for 20 h. The reaction mixture was filtered through Celite, washed with EtOAc (100 mL) and concentrated in vacuo. The residue was purified by chromatography on silica gel (5-30% EtOAc in heptane) to give the title compound (7.47 g, 27.2 mmol, 45% yield) as a colorless oil; ¹ H NMR (400 MHz, chloroform-d) δ 7.43 - 7.29 (m, 5H), 5.14 (s, 2H), 4.57 (p, J = 7.5 Hz, 1H), 2.82 - 2.69 (m, 1H), 2.64 (dtd, J = 10.0, 7.3, 2.6 Hz, 2H), 2.53 (qd, J = 9.8, 9.4, 2.0 Hz, 2H); ¹⁹ F NMR (376 MHz, chloroform-d) δ -59.56.

ＥｔＯＨ（２５０ｍＬ）中のベンジル（１ｓ，３ｓ）－３－（トリフルオロメトキシ）シクロブタン－１－カルボキシレート（７．８５ｇ、２８．６ｍｍｏｌ）および５％のＰｄ／Ｃ（３．０５ｇ、１．４３ｍｍｏｌ）の懸濁液をＨ_２下にて室温で１８時間の間撹拌した。反応混合物をセライトに通して濾過し、真空中で濃縮することで、標題化合物が（５．０９ｇ、２７．６ｍｍｏｌ、９７％の収率）黄色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) δ 4.60 (p, J = 7.5 Hz, 1H), 2.89 - 2.61 (m, 4H), 2.61 - 2.37 (m, 2H); ¹⁹F NMR (376 MHz, chloroform-d) δ -59.62 (3F, s). Intermediate 54 (Step 30.b): (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid

A suspension of benzyl (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylate (7.85 g, 28.6 mmol) and 5% Pd/C (3.05 g, 1.43 mmol) in EtOH (250 mL) was stirred at room temperature under H ₂ for 18 h. The reaction mixture was filtered through Celite and concentrated in vacuo to give the title compound (5.09 g, 27.6 mmol, 97% yield) as a yellow oil; ¹ H NMR (400 MHz, chloroform-d) δ 4.60 (p, J = 7.5 Hz, 1H), 2.89 - 2.61 (m, 4H), 2.61 - 2.37 (m, 2H); ¹⁹ F NMR (376 MHz, chloroform-d) δ -59.62 (3F, s).

無水ＤＭＦ（１０ｍＬ）中の（１ｓ，３ｓ）－３－（トリフルオロメトキシ）シクロブタン－１－カルボン酸（１．００ｇ、５．４３ｍｍｏｌ、中間体５４）の溶液に０℃で、ＨＡＴＵ（２．２７ｇ、５．９７ｍｍｏｌ）、続いてＤＩＰＥＡ（１．９ｍＬ、１０．９ｍｍｏｌ）を添加し、１０分間撹拌した。ベンジルヒドラジンカルボキシレート（０．９０ｇ、５．４３ｍｍｏｌ）を添加し、混合物を室温で２０時間の間撹拌した。反応混合物をＨ_２Ｏ（２０ｍＬ）で希釈し、ＥｔＯＡｃ（２×５０ｍＬ）で抽出した。合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。シリカゲル（ヘプタン中１５～１００％のＥｔＯＡｃ）上のクロマトグラフィーによる精製で、標題化合物が（１．０３ｇ、３．０７ｍｍｏｌ、５６％の収率）白色の粉末として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 9.78 (s, 1H), 9.35 - 8.75 (m, 1H), 7.52 - 7.16 (m, 5H), 5.16 - 4.96 (m, 2H), 4.89 - 4.66 (m, 1H), 2.75 - 2.57 (m, 1H), 2.50 (s, 2H), 2.35 - 2.14 (m, 2H); M/Z: 333 [M+H]⁺, ESI⁺, RT = 0.88 (S2). Step 30. c: ({[(benzyloxy)carbonyl]amino}amino)[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]methanone

To a solution of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (1.00 g, 5.43 mmol, intermediate 54) in anhydrous DMF (10 mL) at 0° C. was added HATU (2.27 g, 5.97 mmol) followed by DIPEA (1.9 mL, 10.9 mmol) and stirred for 10 min. Benzylhydrazine carboxylate (0.90 g, 5.43 mmol) was added and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by chromatography on silica gel (15-100% EtOAc in heptane) gave the title compound (1.03 g, 3.07 mmol, 56% yield) as a white powder; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.78 (s, 1H), 9.35 - 8.75 (m, 1H), 7.52 - 7.16 (m, 5H), 5.16 - 4.96 (m, 2H), 4.89 - 4.66 (m, 1H), 2.75 - 2.57 (m, 1H), 2.50 (s, 2H), 2.35 - 2.14 (m, 2H); M/Z: 333 [M+H] ⁺ , ESI ⁺ , RT = 0.88 (S2).

ＥｔＯＨ（１０ｍＬ）中の（｛［（ベンジルオキシ）カルボニル］アミノ｝アミノ）［（１ｓ，３ｓ）－３－（トリフルオロメトキシ）シクロブチル］メタノン（１．０３ｇ、３．０７ｍｍｏｌ）および１０％のＰｄ／Ｃ（１００ｍｇ、３．０７ｍｍｏｌ）の混合物をＨ_２下にて室温で１８時間の間撹拌した。反応混合物をセライトに通して濾過し、真空中で濃縮することで、標題化合物が（０．５６ｇ、２．６８ｍｍｏｌ、８７％の収率）灰色の固体として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (s, 1H), 4.82 - 4.66 (m, 1H), 4.30 (s, 2H), 2.60 - 2.51 (m, 1H), 2.48 - 2.38 (m, 2H), 2.33 - 2.21 (m, 2H); M/Z: 199 [M+H]⁺, ESI⁺, RT = 0.54 (S2). Intermediate 55 (Step 30.d): (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carbohydrazide

A mixture of ({[(benzyloxy)carbonyl]amino}amino)[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]methanone (1.03 g, 3.07 mmol) and 10% Pd/C (100 mg, 3.07 mmol) in EtOH (10 mL) was stirred at room temperature under _H for 18 h. The reaction mixture was filtered through Celite and concentrated in vacuo to give the title compound (0.56 g, 2.68 mmol, 87% yield) as a grey solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (s, 1H), 4.82 - 4.66 (m, 1H), 4.30 (s, 2H), 2.60 - 2.51 (m, 1H), 2.48 - 2.38 (m, 2H), 2.33 - 2.21 (m, 2H); M/Z: 199 [M+H] ⁺ , ESI ⁺ , RT = 0.54 (S2).

Scheme for Route 31

ＤＣＭ（２ｍＬ）中の２－（４－クロロ－３－フルオロフェノキシ）アセチルクロリド（９０％の純度、７０ｍｇ、０．２８２ｍｍｏｌ、中間体１９）の溶液に、ｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－アミノ－２－｛５－［４－（トリフルオロメチル）フェニル］－１，３，４－オキサジアゾール－２－イル｝ピペリジン－１－カルボキシレート（１２３ｍｇ、０．２８２ｍｍｏｌ、中間体６）およびＤＩＰＥＡ（０．０９９ｍＬ、０．５６５ｍｍｏｌ）を添加し、混合物を室温で４時間の間撹拌した。反応混合物をＨ_２Ｏ（５ｍＬ）で希釈し、ＤＣＭ（３×５ｍＬ）で抽出した。合わせた有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中で濃縮し、シリカゲル（ヘプタン中１７～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（７８ｍｇ、０．１３０ｍｍｏｌ、４６％の収率）茶色の粉末として得られた；Ｍ／Ｚ：４９９、５０１［Ｍ－Ｂｏｃ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝１．２０（Ｓ２）。 [Example 1]
(Step 31.a): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

To a solution of 2-(4-chloro-3-fluorophenoxy)acetyl chloride (90% purity, 70 mg, 0.282 mmol, Intermediate 19) in DCM (2 mL) was added tert-butyl (2R,5S)-5-amino-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (123 mg, 0.282 mmol, Intermediate 6) and DIPEA (0.099 mL, 0.565 mmol) and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with DCM (3×5 mL). The combined organic extracts were dried over MgSO ₄ , concentrated in vacuo, and purified by chromatography on silica gel (17-100% EtOAc in heptane) to give the title compound (78 mg, 0.130 mmol, 46% yield) as a brown powder; M/Z: 499, 501 [M-Boc+H] ⁺ , ESI ⁺ , RT=1.20 (S2).

ＤＣＭ（２ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－｛５－［４－（トリフルオロメチル）フェニル］－１，３，４－オキサジアゾール－２－イル｝ピペリジン－１－カルボキシレート（７８ｍｇ、０．１３０ｍｍｏｌ、実施例１）の溶液に、ＺｎＢｒ_２（８８ｍｇ、０．３９１ｍｍｏｌ）を添加し、混合物を室温で１８時間の間撹拌した。反応混合物を飽和ＮａＨＣＯ_３水溶液（３ｍＬ）で希釈し、ＤＣＭ：ＩＰＡ（８０：２０）（３×３ｍＬ）で抽出した。合わせた有機抽出物を、相分離器を使用して乾燥させ、真空中で濃縮し、分取ＨＰＬＣ（方法４）によって精製することで、標題化合物が（８．０ｍｇ、０．０１５２ｍｍｏｌ、１２％の収率）白色の粉末として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 8.26 - 8.17 (m, 2H), 8.04 - 7.94 (m, 3H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.89 - 6.83 (m, 1H), 4.54 (s, 2H), 4.05 - 3.98 (m, 1H), 3.81 - 3.69 (m, 1H), 3.07 - 2.96 (m, 2H), 2.15 - 2.06 (m, 1H), 1.99 - 1.91 (m, 1H), 1.85 - 1.73 (m, 1H), 1.63 - 1.51 (m, 1H); M/Z: 499, 501 [M+H]⁺, ESI⁺, RT = 2.47 (S4). [Example 2]
(Step 31.b): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide

To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (78 mg, 0.130 mmol, Example 1) in DCM (2 mL) was added ZnBr ₂ (88 mg, 0.391 mmol) and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with saturated aqueous NaHCO ₃ (3 mL) and extracted with DCM:IPA (80:20) (3×3 mL). The combined organic extracts were dried using a phase separator, concentrated in vacuo and purified by preparative HPLC (Method 4) to give the title compound (8.0 mg, 0.0152 mmol, 12% yield) as a white powder; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.26 - 8.17 (m, 2H), 8.04 - 7.94 (m, 3H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.89 - 6.83 (m, 1H), 4.54 (s, 2H), 4.05 - 3.98 (m, 1H), 3.81 - 3.69 (m, 1H), 3.07 - 2.96 M/Z: 499, 501 [M+H] ⁺ , ESI ⁺ , RT = 2.47 (S4).

Scheme for Route 32

ＤＭＦ（１ｍＬ）中の２－（４－クロロフェノキシ）プロパン酸（６９ｍｇ、０．３４３ｍｍｏｌ）の溶液に、ＤＩＰＥＡ（０．１８ｍＬ、１．０３ｍｍｏｌ）およびＨＡＴＵ（１４３ｍｇ、０．３７７ｍｍｏｌ）を添加し、室温で１０分間撹拌した。ｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－アミノ－２－｛５－［４－（トリフルオロメチル）フェニル］－１，３，４－オキサジアゾール－２－イル｝ピペリジン－１－カルボキシレート（１４１ｍｇ、０．３４３ｍｍｏｌ、中間体６）を添加し、混合物を室温で２０時間の間撹拌した。反応混合物をＨ_２Ｏ（５ｍＬ）で希釈し、ＥｔＯＡｃ（３×５ｍＬ）で抽出した。合わせた有機抽出物をブライン（２×１５ｍＬ）で洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中１２～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（９０％の純度、１２３ｍｇ、０．１８６ｍｍｏｌ、５４％の収率）清澄な油状物として得られた；Ｍ／Ｚ：４９５、４９７［Ｍ－Ｂｏｃ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝１．２２（Ｓ２）。 [Example 3]
(Step 32.a): tert-Butyl (2R,5S)-5-[2-(4-chlorophenoxy)propanamido]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

To a solution of 2-(4-chlorophenoxy)propanoic acid (69 mg, 0.343 mmol) in DMF (1 mL) was added DIPEA (0.18 mL, 1.03 mmol) and HATU (143 mg, 0.377 mmol) and stirred at room temperature for 10 min. tert-Butyl (2R,5S)-5-amino-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (141 mg, 0.343 mmol, intermediate 6) was added and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with EtOAc (3×5 mL). The combined organic extracts were washed with brine (2×15 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (12-100% EtOAc in heptane) to give the title compound (90% purity, 123 mg, 0.186 mmol, 54% yield) as a clear oil; M/Z: 495, 497 [M-Boc+H] ⁺ , ESI ⁺ , RT=1.22 (S2).

ＤＣＭ（２ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロフェノキシ）プロパンアミド］－２－｛５－［４－（トリフルオロメチル）フェニル］－１，３，４－オキサジアゾール－２－イル｝ピペリジン－１－カルボキシレート（１０７ｍｇ、０．１８１ｍｍｏｌ、実施例３）の溶液に、ＴＦＡ（７０μＬ、０．９４７ｍｍｏｌ）を添加し、混合物を室温で１８時間の間撹拌した。反応混合物を真空中で濃縮し、飽和ＮａＨＣＯ_３水溶液（１０ｍＬ）中に溶解させ、ＥｔＯＡｃ（３×１０ｍＬ）で抽出した。合わせた有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中で濃縮し、ＤＭＳＯ：ＭｅＣＮ：Ｈ_２Ｏ（６０：３０：１０）を使用して粉砕し、ＭｅＣＮ（１ｍＬ）で洗浄して、標題化合物が（１９ｍｇ、０．０３８３ｍｍｏｌ、２１％の収率）白色の粉末として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 8.25 - 8.19 (m, 2H), 8.03 - 7.94 (m, 3H), 7.36 - 7.30 (m, 2H), 6.96 - 6.89 (m, 2H), 4.72 - 4.64 (m, 1H), 4.02 - 3.95 (m, 1H), 3.74 - 3.63 (m, 1H), 3.03 - 2.91 (m, 2H), 2.13 - 2.00 (m, 1H), 1.96 - 1.82 (m, 1H), 1.82 - 1.69 (m, 1H), 1.60 - 1.46 (m, 1H), 1.43 (d, J = 6.6 Hz, 3H); M/Z: 495, 497 [M+H]⁺, ESI⁺, RT = 2.47 (S4). [Example 4]
(Step 32.b): 2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]propanamide

To a solution of tert-butyl (2R,5S)-5-[2-(4-chlorophenoxy)propanamido]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (107 mg, 0.181 mmol, Example 3) in DCM (2 mL) was added TFA (70 μL, 0.947 mmol) and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, dissolved in saturated aqueous NaHCO ₃ (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over _MgSO4 , concentrated in vacuo, triturated with DMSO:MeCN: _H2O (60:30:10) and washed with MeCN (1 mL) to give the title compound (19 mg, 0.0383 mmol, 21% yield) as a white powder; ^1H NMR (500 MHz, DMSO- _d6 ) δ 8.25 - 8.19 (m, 2H), 8.03 - 7.94 (m, 3H), 7.36 - 7.30 (m, 2H), 6.96 - 6.89 (m, 2H), 4.72 - 4.64 (m, 1H), 4.02 - 3.95 (m, 1H), 3.74 - 3.63 (m, 1H), 3.03 - 2.91 M/Z: 495, 497 [M+H] ⁺ , ESI ⁺ , RT = 2.47 (S4).

Following the synthetic steps of general route 32, the example compounds in Table 9 were synthesized using the corresponding intermediates as illustrated by Example 4.

Scheme for Route 33

ＤＣＭ（５ｍＬ）中の２－［（６－クロロ－５－フルオロピリジン－３－イル）オキシ］酢酸（５０ｍｇ、０．２４３ｍｍｏｌ、中間体１２）の懸濁液に、塩化チオニル（０．１０ｍＬ、１．３７ｍｍｏｌ）を添加し、混合物を４５℃で４時間の間、次いで室温で１８時間の間撹拌した。反応混合物を真空中で濃縮し、ヘプタンを使用して共沸した。結果として生じた残留物をＤＣＭ（５ｍＬ）中に溶解させ、ＤＣＭ（５ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－アミノ－２－［５－（４－クロロフェニル）－１，３，４－オキサジアゾール－２－イル］ピペリジン－１－カルボキシレート（７１ｍｇ、０．１８７ｍｍｏｌ、中間体５３）およびＤＩＰＥＡ（０．１６ｍＬ、０．９３７ｍｍｏｌ）の溶液に添加した。反応混合物を室温で２時間の間撹拌し、次いで、飽和ＮａＨＣＯ_３水溶液（１０ｍＬ）上に注いだ。水溶液をＤＣＭ（２×２０ｍＬ）で抽出し、合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。シリカゲル（ヘプタン中２０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによる精製で、標題化合物が２７ｍｇ、０．０４６７ｍｍｏｌ、２５％の収率）無色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 2.6 Hz, 1H), 7.96 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.14 (dd, J = 8.8, 2.6 Hz, 1H), 4.60 - 4.48 (m, 2H), 4.24 - 4.08 (m, 2H), 2.30 (d, J = 13.0 Hz, 1H), 2.14 - 1.95 (m, 2H), 1.66 (s, 1H), 1.49 (s, 9H), 1.28 - 1.22 (m, 2H); M/Z: 588, 590, 592 [M+Na]⁺, ESI⁺, RT = 1.09 (S2). [Example 6]
(Step 33.a): tert-Butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

To a suspension of 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetic acid (50 mg, 0.243 mmol, Intermediate 12) in DCM (5 mL) was added thionyl chloride (0.10 mL, 1.37 mmol) and the mixture was stirred at 45° C. for 4 h and then at room temperature for 18 h. The reaction mixture was concentrated in vacuo and azeotroped using heptane. The resulting residue was dissolved in DCM (5 mL) and added to a solution of tert-butyl (2R,5S)-5-amino-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (71 mg, 0.187 mmol, Intermediate 53) and DIPEA (0.16 mL, 0.937 mmol) in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 h and then poured onto saturated aqueous NaHCO ₃ solution (10 mL). The aqueous solution was extracted with DCM (2×20 mL) and the combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by chromatography on silica gel (20-100% EtOAc in heptane) afforded the title compound (27 mg, 0.0467 mmol, 25% yield) as a colorless oil; ¹ H NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 2.6 Hz, 1H), 7.96 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.14 (dd, J = 8.8, 2.6 Hz, 1H), 4.60 - 4.48 (m, 2H), 4.24 - 4.08 (m, 2H), 2.30 (d, J = 13.0 Hz, 1H), 2.14 - 1.95 (m, 2H), 1.66 (s, 1H), 1.49 (s, 9H), 1.28 - 1.22 (m, 2H); M/Z: 588, 590, 592 [M+Na] ⁺ , ESI ⁺ , RT = 1.09 (S2).

ＤＣＭ（２ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－｛２－［（６－クロロ－５－フルオロピリジン－３－イル）オキシ］アセトアミド｝－２－［５－（４－クロロフェニル）－１，３，４－オキサジアゾール－２－イル］ピペリジン－１－カルボキシレート（４８ｍｇ、０．０８３０ｍｍｏｌ、実施例６）の溶液に、ＺｎＢｒ_２（５６ｍｇ、０．２４９ｍｍｏｌ）を添加し、反応混合物を室温で４８時間の間撹拌した。反応混合物を真空下で濾過し、ＤＣＭで洗浄して、濾液を真空中で濃縮した。残留物を分取ＨＰＬＣ（方法１）によって精製することで、標題化合物が（１１ｍｇ、０．０２１１ｍｍｏｌ、２５％の収率）白色の固体として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 8.20 (d, J = 7.7 Hz, 1H), 8.09 (d, J = 2.6 Hz, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.75 - 7.68 (m, 2H), 4.68 (s, 2H), 4.38 (s, 1H), 3.90 (s, 1H), 3.22 (d, J = 11.4 Hz, 1H), 2.71 (t, J = 11.1 Hz, 1H), 2.24 (d, J = 11.1 Hz, 1H), 1.99 (d, J = 10.3 Hz, 1H), 1.94 - 1.84 (m, 1H), 1.69 - 1.59 (m, 1H); M/Z: 466, 468, 470 [M+H]⁺, ESI⁺, RT = 2.01 (S4). [Example 7]
(Step 33.b): 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide

To a solution of tert-butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (48 mg, 0.0830 mmol, Example 6) in DCM (2 mL) was added ZnBr ₂ (56 mg, 0.249 mmol) and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered under vacuum, washed with DCM and the filtrate was concentrated in vacuo. The residue was purified by preparative HPLC (Method 1) to give the title compound (11 mg, 0.0211 mmol, 25% yield) as a white solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.20 (d, J = 7.7 Hz, 1H), 8.09 (d, J = 2.6 Hz, 1H), 8.03 (d, J = 8.6 Hz, 2H), 7.75 - 7.68 (m, 2H), 4.68 (s, 2H), 4.38 (s, 1H), 3.90 (s, 1H), 3.22 (d, J = 11.4 Hz, 1H), 2.71 (t, J = 11.1 Hz, 1H), 2.24 (d, J = 11.1 M/Z: 466, 468, 470 [M+H] ⁺ , ESI ⁺ , RT = 2.01 (S4).

Scheme for Route 34

ＤＭＦ（４ｍＬ）中の２－（３，４－ジクロロフェノキシ）酢酸（１０４ｍｇ、０．４７２ｍｍｏｌ）の溶液に、ＨＡＴＵ（１８０ｍｇ、０．４７２ｍｍｏｌ）およびＤＩＰＥＡ（０．２１ｍＬ、１．１８ｍｍｏｌ）を添加し、室温で１０分間撹拌した。ｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－アミノ－２－｛５－［（１ｓ，３ｓ）－３－（トリフルオロメトキシ）シクロブチル］－１，３，４－オキサジアゾール－２－イル｝ピペリジン－１－カルボキシレート（１６０ｍｇ、０．３９４ｍｍｏｌ、中間体４９）を添加し、混合物を室温で３時間の間撹拌した。反応混合物をＨ_２Ｏ（１０ｍＬ）で希釈し、ＥｔＯＡｃ（２×２０ｍＬ）で抽出した。合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（５２％の純度、１０５ｍｇ、０．０８９６ｍｍｏｌ、２３％の収率）黄色の油状物として得られた；Ｍ／Ｚ：５０９、５１１［Ｍ－^ｔブチル＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝１．１７（Ｓ２）。 [Example 8]
(Step 34.a): tert-Butyl (2R,5S)-5-[2-(3,4-dichlorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

To a solution of 2-(3,4-dichlorophenoxy)acetic acid (104 mg, 0.472 mmol) in DMF (4 mL) was added HATU (180 mg, 0.472 mmol) and DIPEA (0.21 mL, 1.18 mmol) and stirred at room temperature for 10 min. tert-Butyl (2R,5S)-5-amino-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (160 mg, 0.394 mmol, Intermediate 49) was added and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (52% purity, 105 mg, 0.0896 mmol, 23% yield) as a yellow oil; M/Z: 509, 511 [M- ^tButyl +H] ⁺ , ESI ⁺ , RT=1.17 (S2).

ＤＣＭ（１ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（３，４－ジクロロフェノキシ）アセトアミド］－２－｛５－［（１ｓ，３ｓ）－３－（トリフルオロメトキシ）シクロブチル］－１，３，４－オキサジアゾール－２－イル｝ピペリジン－１－カルボキシレート（５２％の純度、１０５ｍｇ、０．０８９６ｍｍｏｌ、実施例８）の溶液に、ＺｎＢｒ_２（６１ｍｇ、０．２６９ｍｍｏｌ）を添加し、混合物を室温で６時間の間撹拌した。反応混合物をＨ_２Ｏ（１０ｍＬ）で希釈し、ＤＣＭ／ＩＰＡ（９：１、２×２０ｍＬ）で抽出した。合わせた有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中で濃縮し、分取ＨＰＬＣ（方法３）によって精製することで、標題化合物が（６．７ｍｇ、０．０１３０ｍｍｏｌ、１５％の収率）白色の粉末として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.26 (d, J = 2.9 Hz, 1H), 6.99 (dd, J = 8.9, 2.9 Hz, 1H), 4.98 - 4.87 (m, 1H), 4.53 (s, 2H), 3.86 (dd, J = 10.5, 2.7 Hz, 1H), 3.71 (s, 1H), 3.45 (d, J = 2.1 Hz, 1H), 2.99 (dd, J = 11.8, 2.9 Hz, 1H), 2.89 - 2.80 (m, 3H), 2.43 (s, 3H), 2.00 - 1.97 (m, 1H), 1.92 - 1.88 (m, 1H), 1.69 - 1.64 (m, 1H), 1.54 - 1.49 (m, 1H); M/Z: 509, 511 [M+H]⁺, ESI⁺, RT = 2.42 (S4). [Example 9]
(Step 34.b): 2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide

To a solution of tert-butyl (2R,5S)-5-[2-(3,4-dichlorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (52% purity, 105 mg, 0.0896 mmol, Example 8) in DCM (1 mL) was added ZnBr ₂ (61 mg, 0.269 mmol) and the mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with DCM/IPA (9:1, 2×20 mL). The combined organic extracts were dried over _MgSO4 , concentrated in vacuo and purified by preparative HPLC (Method 3) to give the title compound (6.7 mg, 0.0130 mmol, 15% yield) as a white powder; ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.98 (d, J = 8.0 Hz, 1H), 7.55 (d, J = 8.9 Hz, 1H), 7.26 (d, J = 2.9 Hz, 1H), 6.99 (dd, J = 8.9, 2.9 Hz, 1H), 4.98 - 4.87 (m, 1H), 4.53 (s, 2H), 3.86 (dd, J = 10.5, 2.7 Hz, 1H), 3.71 (s, 1H), 3.45 (d, J = 2.1 Hz, 1H), 2.99 (dd, J = 11.8, 2.9 Hz, 1H), 2.89 - 2.80 (m, 3H), 2.43 (s, 3H), 2.00 - 1.97 (m, 1H), 1.92 - 1.88 (m, 1H), 1.69 - 1.64 (m, 1H), 1.54 - 1.49 (m, 1H); M/Z: 509, 511 [M+H] ⁺ , ESI ⁺ , RT = 2.42 (S4).

Following the synthetic steps of general route 34, the example compounds in Table 10 were synthesized using the corresponding intermediates as illustrated by Example 9.

Scheme for Route 35

ＤＣＭ（１ｍＬ）中の２－（４－クロロ－２－フルオロフェノキシ）酢酸（２０ｍｇ、０．０９９９ｍｍｏｌ）の溶液に、Ｔ３Ｐ（ＥｔＯＡｃ中５０％、７１３μＬ、０．１２０ｍｍｏｌ）およびＤＩＰＥＡ（４１μＬ、０．２３３ｍｍｏｌ）を添加し、室温で１０分間撹拌した。ｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－アミノ－２－［５－（３，３，３－トリフルオロプロポキシ）－１，３，４－オキサジアゾール－２－イル］ピペリジン－１－カルボキシレート（３８ｍｇ、０．１０ｍｍｏｌ、中間体４７）を添加し、結果として生じた混合物を室温で７２時間の間撹拌した。反応混合物をＨ_２Ｏ（１ｍＬ）で希釈し、ＤＣＭ（２ｍＬ）で抽出した。合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮することで、オレンジ色の固体が得られた。該粗材料を精製することなく前に進めた。 [Example 16]
(Step 35.a): tert-Butyl (2R,5S)-5-[2-(4-chloro-2-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

To a solution of 2-(4-chloro-2-fluorophenoxy)acetic acid (20 mg, 0.0999 mmol) in DCM (1 mL) was added T3P (50% in EtOAc, 713 μL, 0.120 mmol) and DIPEA (41 μL, 0.233 mmol) and stirred at room temperature for 10 min. tert-Butyl (2R,5S)-5-amino-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (38 mg, 0.10 mmol, intermediate 47) was added and the resulting mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with H ₂ O (1 mL) and extracted with DCM (2 mL). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo to give an orange solid. The crude material was carried forward without purification.

無水ＤＣＭ（１ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－２－フルオロフェノキシ）アセトアミド］－２－［５－（３，３，３－トリフルオロプロポキシ）－１，３，４－オキサジアゾール－２－イル］ピペリジン－１－カルボキシレート（５７ｍｇ、０．１０ｍｍｏｌ、実施例１６）の溶液に、ＺｎＢｒ_２（９０ｍｇ、０．４０ｍｍｏｌ）を添加し、混合物を室温で１８時間の間撹拌した。反応混合物を飽和ＮａＨＣＯ_３水溶液で希釈し、ＤＣＭ／ＩＰＡ（４：１、２×２ｍＬ）で抽出した。合わせた有機抽出物を真空中で濃縮し、分取ＨＰＬＣ（方法４）によって精製することで、標題化合物が（８８％の純度、１．７ｍｇ、０．００３２ｍｍｏｌ、３％の収率）白色の固体として得られた；¹H NMR (400 MHz, chloroform-d) δ 1.59 - 1.64 (m, 2H), 1.89 - 2.01 (m, 1H), 2.14 (dq, J = 12.8, 4.6, 4.0, 2H), 2.66 (dd, J = 12.0, 7.9, 1H), 2.68 - 2.79 (m, 2H), 3.34 (dd, J = 12.0, 3.5, 1H), 4.02 (dd, J = 8.1, 3.4, 1H), 4.08 (ddt, J = 12.3, 8.2, 4.1, 1H), 4.53 (s, 2H), 4.72 (t, J = 6.2, 2H), 6.86 - 6.97 (m, 2H), 7.11 (ddd, J = 8.7, 2.4, 1.7, 1H), 7.19 (dd, J = 10.6, 2.5, 1H); M/Z: 467, 469 [M+H]⁺, ESI⁺, RT = 1.98 (S4). [Example 17]
(Step 35.b): 2-(4-chloro-2-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide

To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-2-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (57 mg, 0.10 mmol, Example 16) in anhydrous DCM (1 mL) was added ZnBr ₂ (90 mg, 0.40 mmol) and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with saturated aqueous NaHCO ₃ and extracted with DCM/IPA (4:1, 2×2 mL). The combined organic extracts were concentrated in vacuo and purified by preparative HPLC (Method 4) to give the title compound (88% purity, 1.7 mg, 0.0032 mmol, 3% yield) as a white solid; ¹ H NMR (400 MHz, chloroform-d) δ 1.59 - 1.64 (m, 2H), 1.89 - 2.01 (m, 1H), 2.14 (dq, J = 12.8, 4.6, 4.0, 2H), 2.66 (dd, J = 12.0, 7.9, 1H), 2.68 - 2.79 (m, 2H), 3.34 (dd, J = 12.0, 3.5, 1H), 4.02 (dd, J = 8.1, 3.4, 1H), 4.08 (ddt, J = 12.3, 8.2, 4.1, 1H), 4.53 (s, 2H), 4.72 (t, J = 6.2, 2H), 6.86 - 6.97 (m, 2H), 7.11 (ddd, J = 8.7, 2.4, 1.7, 1H), 7.19 (dd, J = 10.6, 2.5, 1H); M/Z: 467, 469 [M+H] ⁺ , ESI ⁺ , RT = 1.98 (S4).

Following the synthetic steps of general route 35, the example compounds in Table 11 were synthesized using the corresponding intermediates as exemplified by Example 17.

Scheme for Route 36

ＤＭＦ（１ｍＬ）中の（２Ｒ，４Ｓ）－１－［（ｔｅｒｔ－ブトキシ）カルボニル］－４－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］ピロリジン－２－カルボン酸（８０％の純度、２００ｍｇ、０．３８４ｍｍｏｌ、中間体３４）、４－クロロベンゾヒドラジド（６５ｍｇ、０．３８４ｍｍｏｌ）およびＤＩＰＥＡ（０．０８０ｍＬ、０．４６１ｍｍｏｌ）の溶液に、Ｔ３Ｐ（ＥｔＯＡｃ中５０％、０．２５ｍＬ、０．４２２ｍｍｏｌ）を添加し、混合物を室温で１時間の間撹拌した。反応混合物をＨ_２Ｏ（２０ｍＬ）で希釈し、ＥｔＯＡｃ（２×２０ｍＬ）で抽出した。合わせた有機抽出物をブラインで洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（８９％の純度、１５８ｍｇ、０．２４７ｍｍｏｌ、６４％の収率）淡黄色のガムとして得られた；¹H NMR (400 MHz, DMSO-d₆) δ 10.52 (d, J = 48.5 Hz, 1H), 10.05 (d, J = 9.9 Hz, 1H), 8.34 (t, J = 6.4 Hz, 1H), 7.98 - 7.85 (m, 2H), 7.58 (dd, J = 8.5, 4.7 Hz, 2H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (d, J = 11.5 Hz, 1H), 6.91 - 6.80 (m, 1H), 4.55 (s, 2H), 4.52 - 4.39 (m, 1H), 4.34 (dq, J = 12.6, 4.4 Hz, 1H), 3.73 - 3.59 (m, 1H), 3.25 - 3.11 (m, 1H), 2.31 - 2.11 (m, 2H), 1.40 (s, 9H); M/Z: 469, 471, 473 [M-Boc+H]⁺, ESI⁺, RT = 0.95 (S2). Step 36. a: tert-Butyl (2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{[(4-chlorophenyl)formohydrazide]carbonyl}pyrrolidine-1-carboxylate

To a solution of (2R,4S)-1-[(tert-butoxy)carbonyl]-4-[2-(4-chloro-3-fluorophenoxy)acetamido]pyrrolidine-2-carboxylic acid (80% purity, 200 mg, 0.384 mmol, intermediate 34), 4-chlorobenzohydrazide (65 mg, 0.384 mmol) and DIPEA (0.080 mL, 0.461 mmol) in DMF (1 mL) was added T3P (50% in EtOAc, 0.25 mL, 0.422 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H ₂ O (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (89% purity, 158 mg, 0.247 mmol, 64% yield) as a pale yellow gum; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.52 (d, J = 48.5 Hz, 1H), 10.05 (d, J = 9.9 Hz, 1H), 8.34 (t, J = 6.4 Hz, 1H), 7.98 - 7.85 (m, 2H), 7.58 (dd, J = 8.5, 4.7 Hz, 2H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (d, J = 11.5 Hz, 1H), 6.91 - 6.80 (m, 1H), 4.55 (s, 2H), 4.52 - 4.39 (m, 1H), 4.34 (dq, J = 12.6, 4.4 Hz, 1H), 3.73 - 3.59 (m, 1H), 3.25 - 3.11 (m, 1H), 2.31 - 2.11 (m, 2H), 1.40 (s, 9H); M/Z: 469, 471, 473 [M-Boc+H] ⁺ , ESI ⁺ , RT = 0.95 (S2).

ＡＣＮ（２ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，４Ｓ）－４－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－｛［（４－クロロフェニル）ホルモヒドラジド］カルボニル｝ピロリジン－１－カルボキシレート（８９％の純度、１５８ｍｇ、０．２４７ｍｍｏｌ）、Ｋ_２ＣＯ_３（２０５ｍｇ、１．４８ｍｍｏｌ）およびＴｓＣｌ（０．０１２ｍＬ、０．７４１ｍｍｏｌ）の懸濁液を、８０℃で２．５時間の間撹拌した。反応混合物をＥｔＯＡｃ（３０ｍＬ）とＨ_２Ｏ（２０ｍＬ）との間で分配した。有機層を単離し、ブラインで洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（１１９ｍｇ、０．２０８ｍｍｏｌ、８４％の収率）淡黄色のガムとして得られた；¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.87 (dd, J = 9.0, 1.7 Hz, 1H), 5.30 - 5.18 (m, 1H), 4.66 - 4.47 (m, 3H), 3.82 - 3.69 (m, 1H), 3.44 - 3.40 (m, 1H), 2.44 - 2.35 (m, 2H), 1.42 - 1.18 (m, 9H); M/Z: 595, 597 [M+MeCN+H]⁺, ESI⁺, RT = 1.11 (S2). [Example 30]
(Step 36.b): tert-Butyl (2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]pyrrolidine-1-carboxylate

A suspension of tert-butyl (2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{[(4-chlorophenyl)formohydrazide]carbonyl}pyrrolidine-1-carboxylate (89% purity, 158 mg, 0.247 mmol), K ₂ CO ₃ (205 mg, 1.48 mmol) and TsCl (0.012 mL, 0.741 mmol) in ACN (2 mL) was stirred at 80° C. for 2.5 h. The reaction mixture was partitioned between EtOAc (30 mL) and H ₂ O (20 mL). The organic layer was isolated, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (119 mg, 0.208 mmol, 84% yield) as a pale yellow gum; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.49 (s, 1H), 8.01 (d, J = 8.5 Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.87 (dd, J = 9.0, 1.7 Hz, 1H), 5.30 - 5.18 (m, 1H), 4.66 - 4.47 (m, 3H), 3.82 - 3.69 (m, 1H), 3.44 - 3.40 (m, 1H), 2.44 - 2.35 (m, 2H), 1.42 - 1.18 (m, 9H); M/Z: 595, 597 [M+MeCN+H] ⁺ , ESI ⁺ , RT = 1.11 (S2).

ＤＣＭ（２．５ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，４Ｓ）－４－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－［５－（４－クロロフェニル）－１，３，４－オキサジアゾール－２－イル］ピロリジン－１－カルボキシレート（１１９ｍｇ、０．２０７ｍｍｏｌ、実施例３０）およびＴＦＡ（０．１５ｍＬ、２．０７ｍｍｏｌ）の溶液を室温で４時間の間撹拌した。反応混合物をＤＣＭと飽和ＮａＨＣＯ_３水溶液との間で分配し、相分離器を使用して有機層を単離し、真空中で濃縮した。残留物を分取ＨＰＬＣ（方法３）によって精製すること、および次いで、Ｅｔ_２Ｏを使用して粉砕することで、標題化合物が（４４ｍｇ、０．０９６５ｍｍｏｌ、４７％の収率）白色の固体として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 8.26 (d, J = 7.2 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.72 - 7.65 (m, 2H), 7.51 (t, J = 8.9 Hz, 1H), 7.10 (dd, J = 11.4, 2.8 Hz, 1H), 6.90 - 6.85 (m, 1H), 4.65 (s, 1H), 4.55 (s, 2H), 4.46 - 4.37 (m, 1H), 3.16 - 3.07 (m, 2H), 2.87 - 2.79 (m, 1H), 2.44 - 2.38 (m, 1H), 2.19 - 2.10 (m, 1H); M/Z: 451, 453, 455 [M+H]⁺, ESI⁺, RT = 2.26 (S4). [Example 31]
(Step 36.c): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,5R)-5-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]pyrrolidin-3-yl]acetamide

A solution of tert-butyl (2R,4S)-4-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]pyrrolidine-1-carboxylate (119 mg, 0.207 mmol, Example 30) and TFA (0.15 mL, 2.07 mmol) in DCM (2.5 mL) was stirred at room temperature for 4 h. The reaction mixture was partitioned between DCM and saturated aqueous NaHCO ₃ and the organic layer was isolated using a phase separator and concentrated in vacuo. The residue was purified by preparative HPLC (Method 3) and then triturated with Et ₂ O to give the title compound (44 mg, 0.0965 mmol, 47% yield) as a white solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.26 (d, J = 7.2 Hz, 1H), 8.04 - 7.98 (m, 2H), 7.72 - 7.65 (m, 2H), 7.51 (t, J = 8.9 Hz, 1H), 7.10 (dd, J = 11.4, 2.8 Hz, 1H), 6.90 - 6.85 (m, 1H), 4.65 (s, 1H), 4.55 (s, 2H), 4.46 - 4.37 (m, 1H), 3.16 - 3.07 (m, 2H), 2.87 - 2.79 (m, 1H), 2.44 - 2.38 (m, 1H), 2.19 - 2.10 (m, 1H); M/Z: 451, 453, 455 [M+H] ⁺ , ESI ⁺ , RT = 2.26 (S4).

Scheme for Route 37

無水ＤＭＦ（６ｍＬ）中の（２Ｒ，５Ｓ）－１－［（ｔｅｒｔ－ブトキシ）カルボニル］－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］ピペリジン－２－カルボン酸（５００ｍｇ、１．１０ｍｍｏｌ、中間体２２）の溶液に、ＤＩＰＥＡ（０．４０ｍＬ、２．２９ｍｍｏｌ）およびＨＡＴＵ（５０３ｍｇ、１．３２ｍｍｏｌ）を添加し、室温で１０分間撹拌した。（３，３，３－トリフルオロプロポキシ）カルボヒドラジド（２７３ｍｇ、１．４３ｍｍｏｌ、中間体３８）を添加し、混合物を室温で１２時間の間撹拌した。反応混合物をＥｔＯＡｃ（２０ｍＬ）で希釈し、ブライン（２０ｍＬ）で洗浄した。合わせた有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中で濃縮し、シリカゲル（ヘプタン中０～８０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（９１％の純度、６４６ｍｇ、１．００ｍｍｏｌ、９１％の収率）無色の油状物として得られた；Ｍ／Ｚ：４８５、４８７［Ｍ－Ｂｏｃ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝０．９６（Ｓ２）。 Step 37. a: tert-Butyl (2R,5S)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-2-[(3,3,3-trifluoropropoxycarbonylamino)carbamoyl]piperidine-1-carboxylate

To a solution of (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-2-carboxylic acid (500 mg, 1.10 mmol, Intermediate 22) in anhydrous DMF (6 mL) was added DIPEA (0.40 mL, 2.29 mmol) and HATU (503 mg, 1.32 mmol) and stirred at room temperature for 10 min. (3,3,3-trifluoropropoxy)carbohydrazide (273 mg, 1.43 mmol, Intermediate 38) was added and the mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with brine (20 mL). The combined organic extracts were dried over _MgSO4 , concentrated in vacuo, and purified by chromatography on silica gel (0-80% EtOAc in heptane) to give the title compound (91% purity, 646 mg, 1.00 mmol, 91% yield) as a colorless oil; M/Z: 485, 487 [M-Boc+H] ⁺ , ESI ⁺ , RT=0.96 (S2).

ＡＣＮ（５ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［［２－（４－クロロ－３－フルオロ－フェノキシ）アセチル］アミノ］－２－［（３，３，３－トリフルオロプロポキシカルボニルアミノ）カルバモイル］ピペリジン－１－カルボキシレート（９１％の純度、６４６ｍｇ、１．０ｍｍｏｌ）、Ｋ_２ＣＯ_３（８３３ｍｇ、６．０３ｍｍｏｌ）およびＴｓＣｌ（５７６ｍｇ、３．０２ｍｍｏｌ）の懸濁液を８０℃で３時間の間撹拌した。反応混合物をＥｔＯＡｃ（２０ｍＬ）で希釈し、ブライン（２０ｍＬ）で洗浄した。有機層をＭｇＳＯ_４上で乾燥させ、真空中で濃縮し、シリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（２５２ｍｇ、０．４４０ｍｍｏｌ、４４％の収率）白色の粉末として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (d, J = 7.0 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.04 (dd, J = 11.4, 2.9 Hz, 1H), 6.82 (ddd, J = 9.0, 2.8, 1.1 Hz, 1H), 5.38 (s, 1H), 4.65 (t, J = 5.7 Hz, 2H), 4.62 - 4.52 (m, 2H), 3.96 - 3.85 (m, 2H), 2.99 - 2.85 (m, 3H), 2.25 - 2.11 (m, 1H), 2.03 - 1.94 (m, 1H), 1.86 - 1.73 (m, 1H), 1.63 (d, J = 13.5 Hz, 1H), 1.37 (s, 9H); M/Z: 467, 469 [M-Boc+H]⁺, ESI⁺, RT = 1.07 (S2). [Example 32]
(Step 37.b): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

A suspension of tert-butyl (2R,5S)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-2-[(3,3,3-trifluoropropoxycarbonylamino)carbamoyl]piperidine-1-carboxylate (91% purity, 646 mg, 1.0 mmol), K ₂ CO ₃ (833 mg, 6.03 mmol) and TsCl (576 mg, 3.02 mmol) in ACN (5 mL) was stirred for 3 h at 80° C. The reaction mixture was diluted with EtOAc (20 mL) and washed with brine (20 mL). The organic layer was dried over _MgSO4 , concentrated in vacuo, and purified by chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (252 mg, 0.440 mmol, 44% yield) as a white powder; ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.08 (d, J = 7.0 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.04 (dd, J = 11.4, 2.9 Hz, 1H), 6.82 (ddd, J = 9.0, 2.8, 1.1 Hz, 1H), 5.38 (s, 1H), 4.65 (t, J = 5.7 Hz, 2H), 4.62 - 4.52 (m, 2H), 3.96 - 3.85 (m, 2H), 2.99 - 2.85 (m, 3H), 2.25 - 2.11 (m, 1H), 2.03 - 1.94 (m, 1H), 1.86 - 1.73 (m, 1H), 1.63 (d, J = 13.5 Hz, 1H), 1.37 (s, 9H); M/Z: 467, 469 [M-Boc+H] ⁺ , ESI ⁺ , RT = 1.07 (S2).

ＤＣＭ（２ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－［５－（３，３，３－トリフルオロプロポキシ）－１，３，４－オキサジアゾール－２－イル］ピペリジン－１－カルボキシレート（１０７ｍｇ、０．１８５ｍｍｏｌ、実施例３２）およびＴＦＡ（０．１４ｍＬ、１．８５ｍｍｏｌ）の溶液を室温で６時間の間撹拌した。反応混合物をＤＣＭ（５ｍＬ）と飽和ＮａＨＣＯ_３水溶液（５ｍＬ）との間で分配した。有機層を単離し、真空中で濃縮し、分取ＨＰＬＣ（方法３）によって精製することで、標題化合物が（１５ｍｇ、０．０２９８ｍｍｏｌ、１６％の収率）白色の固体として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 7.97 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.74 - 4.58 (m, 2H), 4.53 (s, 2H), 3.79 (dd, J = 10.5, 2.5 Hz, 1H), 3.76 - 3.62 (m, 1H), 3.06 - 2.80 (m, 3H), 2.47 - 2.41 (m, 1H), 2.05 - 1.81 (m, 2H), 1.76 - 1.59 (m, 1H), 1.50 (qd, J = 12.3, 3.7 Hz, 1H); M/Z: 467, 469 [M+H]⁺, ESI⁺, RT = 3.12 (S6). [Example 33]
(Step 37.c): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide

A solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (107 mg, 0.185 mmol, Example 32) and TFA (0.14 mL, 1.85 mmol) in DCM (2 mL) was stirred at room temperature for 6 h. The reaction mixture was partitioned between DCM (5 mL) and saturated _aqueous NaHCO3 (5 mL). The organic layer was isolated, concentrated in vacuo and purified by preparative HPLC (Method 3) to give the title compound (15 mg, 0.0298 mmol, 16% yield) as a white solid; ^1H NMR (400 MHz, DMSO- _d6 ) δ 7.97 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.9, 1.2 Hz, 1H), 4.74 - 4.58 (m, 2H), 4.53 (s, 2H), 3.79 (dd, J = 10.5, 2.5 Hz, 1H), 3.76 - 3.62. M/Z: 467, 469 [M+H] ⁺ , ESI ⁺ , RT = 3.12 (S6).

Following the synthetic steps of general route 37, the example compounds in Table 12 were synthesized using the corresponding intermediates as exemplified by Example 33.

Scheme for Route 38

無水ＤＭＦ（５ｍＬ）中の（２Ｓ，５Ｒ）－１－［（ｔｅｒｔ－ブトキシ）カルボニル］－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］ピペリジン－２－カルボン酸（４５０ｍｇ、１．０４ｍｍｏｌ、中間体２５）の溶液に、ＨＡＴＵ（４７７ｍｇ、１．２５ｍｍｏｌ）およびＤＩＰＥＡ（０．３６ｍＬ、２．０９ｍｍｏｌ）を添加し、混合物を室温で１０分間撹拌した。（３，３，３－トリフルオロプロポキシ）カルボヒドラジド（９０％の純度、２６０ｍｇ、１．３６ｍｍｏｌ、中間体３８）を次いで添加し、混合物を室温で１８時間の間撹拌した。反応混合物をＥｔＯＡｃ（２５ｍＬ）と１ＭのＨＣｌ水溶液（２５ｍＬ）との間で分配した。有機層を単離し、飽和水性ＮａＨＣＯ_３（２５ｍＬ）およびブライン（２×２５ｍＬ）で洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中２０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（８５％の純度、２６８ｍｇ、０．３８９ｍｍｏｌ、３７％の収率）清澄な油状物として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 9.78 (s, 1H), 9.22 (s, 1H), 7.98 (d, J = 7.1 Hz, 1H), 7.48 (m 1H), 7.05 (dd, J = 11.4, 2.8 Hz, 1H), 6.82 (dd, J = 8.9, 1.8 Hz, 1H), 4.74 - 4.44 (m, 3H), 4.22 (m, 2H), 3.87 (m, 2H), 2.63 (m, 2H), 2.02 (m, 2H), 1.85 (m, 1H), 1.58 (s, 2H), 1.37 (s, 9H); M/Z: 485, 487 [M-Boc+H]⁺, ESI⁺, RT = 0.96 (S2). Step 38. a: tert-Butyl (2S,5R)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{N'-[(3,3,3-trifluoropropoxy)carbonyl]hydrazinecarbonyl}piperidine-1-carboxylate

To a solution of (2S,5R)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-2-carboxylic acid (450 mg, 1.04 mmol, Intermediate 25) in anhydrous DMF (5 mL) was added HATU (477 mg, 1.25 mmol) and DIPEA (0.36 mL, 2.09 mmol) and the mixture was stirred at room temperature for 10 min. (3,3,3-trifluoropropoxy)carbohydrazide (90% purity, 260 mg, 1.36 mmol, Intermediate 38) was then added and the mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between EtOAc (25 mL) and 1 M aqueous HCl (25 mL). The organic layer was isolated, washed with saturated aqueous NaHCO ₃ (25 mL) and brine (2×25 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (20-100% EtOAc in heptane) to give the title compound (85% purity, 268 mg, 0.389 mmol, 37% yield) as a clear oil; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.78 (s, 1H), 9.22 (s, 1H), 7.98 (d, J = 7.1 Hz, 1H), 7.48 (m 1H), 7.05 (dd, J = 11.4, 2.8 Hz, 1H), 6.82 (dd, J = 8.9, 1.8 Hz, 1H), 4.74 - 4.44 (m, 3H), 4.22 (m, 2H), 3.87 (m, 2H), 2.63 (m, 2H), 2.02 (m, 2H), 1.85 (m, 1H), 1.58 (s, 2H), 1.37 (s, 9H); M/Z: 485, 487 [M-Boc+H] ⁺ , ESI ⁺ , RT = 0.96 (S2).

ＡＣＮ（２．５ｍＬ）中のｔｅｒｔ－ブチル（２Ｓ，５Ｒ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－｛Ｎ’－［（３，３，３－トリフルオロプロポキシ）カルボニル］ヒドラジンカルボニル｝ピペリジン－１－カルボキシレート（８５％の純度、２６５ｍｇ、０．３８５ｍｍｏｌ）、Ｋ_２ＣＯ_３（３１９ｍｇ、２．３１ｍｍｏｌ）およびＴｓＣｌ（２２０ｍｇ、１．１６ｍｍｏｌ）の懸濁液を８０℃で２４時間の間撹拌した。反応混合物をＨ_２Ｏ（１０ｍＬ）で希釈し、ＥｔＯＡｃ（３×１０ｍＬ）で抽出した。合わせた有機抽出物をブライン（３×１０ｍＬ）で洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。結果として生じた残留物をシリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（８８％の純度、６８ｍｇ、０．１０６ｍｍｏｌ、２７％の収率）茶色の油状物として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 8.08 (d, J = 7.0 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.04 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 - 6.78 (m, 1H), 5.38 (s, 1H), 4.65 (t, J = 5.7 Hz, 2H), 4.62 - 4.51 (m, 2H), 3.96 - 3.84 (m, 2H), 3.02 - 2.85 (m, 2H), 2.24 - 2.13 (m, 1H), 2.04 - 1.94 (m, 2H), 1.84 - 1.74 (m, 1H), 1.68 - 1.57 (m, 1H), 1.38 (s, 9H); M/Z: 467, 469 [M-Boc+H]⁺, ESI⁺, RT = 1.31 (S1). [Example 41]
(Step 38.b): tert-Butyl (2S,5R)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

A suspension of tert-butyl (2S,5R)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{N'-[(3,3,3-trifluoropropoxy)carbonyl]hydrazinecarbonyl}piperidine-1-carboxylate (85% purity, 265 mg, 0.385 mmol), _K2CO3 (319 mg, 2.31 mmol) and TsCl (220 mg, 1.16 mmol) in ACN (2.5 mL) was stirred at 80° C. for 24 _h . The reaction mixture was diluted with _H2O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (3×10 mL), dried over _MgSO4 and concentrated in vacuo. The resulting residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (88% purity, 68 mg, 0.106 mmol, 27% yield) as a brown oil; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.08 (d, J = 7.0 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.04 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 - 6.78 (m, 1H), 5.38 (s, 1H), 4.65 (t, J = 5.7 Hz, 2H), 4.62 - 4.51 (m, 2H), 3.96 - 3.84 (m, 2H), 3.02 - 2.85 (m, 2H), 2.24 - 2.13 (m, 1H), 2.04 - 1.94 (m, 2H), 1.84 - 1.74 (m, 1H), 1.68 - 1.57 (m, 1H), 1.38 (s, 9H); M/Z: 467, 469 [M-Boc+H] ⁺ , ESI ⁺ , RT = 1.31 (S1).

ＤＣＭ（１ｍＬ）中のｔｅｒｔ－ブチル（２Ｓ，５Ｒ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－［５－（３，３，３－トリフルオロプロポキシ）－１，３，４－オキサジアゾール－２－イル］ピペリジン－１－カルボキシレート（８８％の純度、５５ｍｇ、０．０８５４ｍｍｏｌ）の溶液に、ＺｎＢｒ_２（７７ｍｇ、０．３４１ｍｍｏｌ）を添加し、混合物をＮ_２下にて室温で１８時間の間撹拌した。反応混合物を飽和ＮａＨＣＯ_３水溶液（３ｍＬ）で希釈し、ＤＣＭ：ＩＰＡ（８０：２０）（３×３ｍＬ）で抽出した。合わせた有機抽出物をブライン（５ｍＬ）で洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。結果として生じた残留物を分取ＨＰＬＣ（方法３）によって精製することで、標題化合物が（１２ｍｇ、０．０２４９ｍｍｏｌ、２９％の収率）白色の粉末として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 7.96 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 8.8 Hz, 1H), 7.07 (dd, J = 11.4, 2.5 Hz, 1H), 6.87 - 6.81 (m, 1H), 4.64 (t, J = 5.5 Hz, 2H), 4.52 (s, 2H), 3.80 - 3.63 (m, 2H), 3.02 - 2.83 (m, 3H), 2.83 - 2.75 (m, 1H), 2.46 - 2.39 (m, 1H), 2.00 - 1.83 (m, 2H), 1.70 - 1.57 (m, 1H), 1.54 - 1.43 (m, 1H); M/Z: 467, 469, [M+H]⁺, ESI⁺, RT = 3.12 (S6). [Example 42]
(Step 38.c): 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide

To a solution of tert-butyl (2S,5R)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (88% purity, 55 mg, 0.0854 mmol) in DCM (1 mL) was added ZnBr ₂ (77 mg, 0.341 mmol) and the mixture was stirred at room temperature under N ₂ for 18 h. The reaction mixture was diluted with saturated aqueous NaHCO ₃ (3 mL) and extracted with DCM:IPA (80:20) (3×3 mL). The combined organic extracts were washed with brine (5 mL), dried over MgSO ₄ and concentrated in vacuo. The resulting residue was purified by preparative HPLC (Method 3) to give the title compound (12 mg, 0.0249 mmol, 29% yield) as a white powder; ^1H NMR (500 MHz, DMSO- _d6 ) δ 7.96 (d, J = 7.8 Hz, 1H), 7.49 (t, J = 8.8 Hz, 1H), 7.07 (dd, J = 11.4, 2.5 Hz, 1H), 6.87 - 6.81 (m, 1H), 4.64 (t, J = 5.5 Hz, 2H), 4.52 (s, 2H), 3.80 - 3.63 (m, 2H), 3.02 - 2.83 (m, 3H), 2.83 - 2.75 (m, 1H), 2.46 - 2.39 (m, 1H), 2.00 - 1.83 (m, 2H), 1.70 - 1.57 (m, 1H), 1.54 - 1.43 (m, 1H); M/Z: 467, 469, [M+H] ⁺ , ESI ⁺ , RT = 3.12 (S6).

Following the synthetic steps of general route 38, the example compounds in Table 13 were synthesized using the corresponding intermediates as exemplified by Example 42.

Scheme for Route 39

[Example 44]
A solution of CSA (200 μL, 0.0172 mmol), 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide (40 mg, 0.0860 mmol, Example 35) and 1,3,5-trioxane (25 μL, 0.215 mmol) in DCE (0.5 mL) was stirred at room temperature under _N2 for 45 min. STAB (55 mg, 0.258 mmol) was added and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was diluted with DCM (5 mL) and saturated _aqueous NaHCO3 (5 mL). The organic layer was isolated, concentrated in vacuo and purified by preparative HPLC (Method 2) to give the title compound (9.8 mg, 0.0194 mmol, 23% yield) as a white solid; ^1H NMR (500 MHz, DMSO- _d6 ) δ 8.10 (d, J = 8.0 Hz, 1H), 8.06 - 7.98 (m, 2H), 7.73 - 7.64 (m, 2H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.86 (dd, J = 8.9, 2.0 Hz, 1H), 4.55 (s, 2H), 4.00 - 3.86 (m, 1H), 3.52 (dd, J M/Z: 479, 481, 482 [M+H] ⁺ , ESI ⁺ , RT = 3.00 (S4).

Following general route 39, the example compounds in Table 14 were synthesized using the corresponding intermediates as exemplified by Example 44.

Scheme for Route 40

ＤＭＦ（５ｍＬ）中の（２Ｓ，５Ｒ）－５－｛［（ｔｅｒｔ－ブトキシ）カルボニル］アミノ｝－１－エチルピペリジン－２－カルボン酸（５０ｍｇ、０．１８３ｍｍｏｌ、中間体４３）の溶液に０℃で、４－クロロベンゾヒドラジド（４１ｍｇ、０．２３８ｍｍｏｌ）、続いてＨＡＴＵ（８３ｍｇ、０．２２０ｍｍｏｌ）およびＤＩＰＥＡ（０．０６４ｍＬ、０．３６６ｍｍｏｌ）を添加し、混合物を室温で３時間の間撹拌した。反応混合物をＨ_２Ｏ（３０ｍＬ）で希釈し、ＥｔＯＡｃ（２×２０ｍＬ）で抽出した。合わせた有機抽出物をブライン（３０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中１０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（７５％の純度、１００ｍｇ、０．１７７ｍｍｏｌ、９６％の収率）得られた；Ｍ／Ｚ：４２５、４２７［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝０．８７（Ｓ１）。 Step 40. a: tert-Butyl N-[(3R,6S)-6-{[(4-chlorophenyl)formohydrazide]carbonyl}-1-ethylpiperidin-3-yl]carbamate

To a solution of (2S,5R)-5-{[(tert-butoxy)carbonyl]amino}-1-ethylpiperidine-2-carboxylic acid (50 mg, 0.183 mmol, intermediate 43) in DMF (5 mL) at 0° C. was added 4-chlorobenzohydrazide (41 mg, 0.238 mmol), followed by HATU (83 mg, 0.220 mmol) and DIPEA (0.064 mL, 0.366 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (10-100% EtOAc in heptane) to give the title compound (75% purity, 100 mg, 0.177 mmol, 96% yield); M/Z: 425, 427 [M+H] ⁺ , ESI ⁺ , RT=0.87 (S1).

無水ＡＣＮ（１０ｍＬ）中のｔｅｒｔ－ブチルＮ－［（３Ｒ，６Ｓ）－６－｛［（４－クロロフェニル）ホルモヒドラジド］カルボニル｝－１－エチルピペリジン－３－イル］カルバメート（７５％の純度、１００ｍｇ、０．１７７ｍｍｏｌ）の溶液に、ＴｓＣｌ（１０１ｍｇ、０．５３０ｍｍｏｌ）、続いてＤＩＰＥＡ（０．０９２ｍＬ、０．５３０ｍｍｏｌ）を添加し、混合物を室温で１６時間の間撹拌した。１５％のＮＨ_４ＯＨ水溶液（１０ｍＬ）を添加し、反応混合物を真空中で濃縮した。残留物をＨ_２Ｏ（２０ｍＬ）中に溶解させ、ＤＣＭ（２×３０ｍＬ）で抽出した。合わせた有機抽出物をブライン（３０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中１０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（８１％の純度、８２ｍｇ、０．１６３ｍｍｏｌ、９２％の収率）白色の固体として得られた；Ｍ／Ｚ：４０７、４０９［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝１．０２（Ｓ１）。 Step 40. b: tert-Butyl N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethylpiperidin-3-yl]carbamate

To a solution of tert-butyl N-[(3R,6S)-6-{[(4-chlorophenyl)formohydrazide]carbonyl}-1-ethylpiperidin-3-yl]carbamate (75% purity, 100 mg, 0.177 mmol) in anhydrous ACN (10 mL) was added TsCl (101 mg, 0.530 mmol) followed by DIPEA (0.092 mL, 0.530 mmol) and the mixture was stirred at room temperature for 16 h. 15% aqueous NH ₄ OH (10 mL) was added and the reaction mixture was concentrated in vacuo. The residue was dissolved in H ₂ O (20 mL) and extracted with DCM (2×30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (10-100% EtOAc in heptane) to give the title compound (81% purity, 82 mg, 0.163 mmol, 92% yield) as a white solid; M/Z: 407, 409 [M+H] ⁺ , ESI ⁺ , RT=1.02 (S1).

ＤＣＭ（１ｍＬ）中のｔｅｒｔ－ブチルＮ－［（３Ｒ，６Ｓ）－６－［５－（４－クロロフェニル）－１，３，４－オキサジアゾール－２－イル］－１－エチルピペリジン－３－イル］カルバメート（８１％の純度、８２ｍｇ、０．１６３ｍｍｏｌ）の溶液に０℃で、ＴＦＡ（１．０ｍＬ、１３．５ｍｍｏｌ）を添加し、混合物を室温で３時間の間撹拌した。反応混合物を真空中で濃縮することで、標題化合物が（２８％の純度、１６０ｍｇ、０．１０６ｍｍｏｌ、６５％の収率）ベージュのガムとして得られた；Ｍ／Ｚ：３０７、３０９［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝０．８４（Ｓ１）。 Step 40. c: (3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethylpiperidin-3-amine; trifluoroacetic acid

To a solution of tert-butyl N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethylpiperidin-3-yl]carbamate (81% purity, 82 mg, 0.163 mmol) in DCM (1 mL) at 0° C. was added TFA (1.0 mL, 13.5 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated in vacuo to give the title compound (28% purity, 160 mg, 0.106 mmol, 65% yield) as a beige gum; M/Z: 307, 309 [M+H] ⁺ , ESI ⁺ , RT=0.84 (S1).

ＤＣＭ（５ｍＬ）中の（３Ｒ，６Ｓ）－６－［５－（４－クロロフェニル）－１，３，４－オキサジアゾール－２－イル］－１－エチル－ピペリジン－３－アミントリフルオロ酢酸（２８％の純度、１６０ｍｇ、０．１０６ｍｍｏｌ）の溶液に０℃で、ＤＩＰＥＡ（０．０５６ｍＬ、０．３１９ｍｍｏｌ）、続いてＤＣＭ（１ｍＬ）中の２－（４－クロロ－３－フルオロ－フェノキシ）アセチルクロリド（２９ｍｇ、０．１２８ｍｍｏｌ、中間体１９）の溶液を添加し、混合物を室温で５時間の間撹拌した。反応混合物をＨ_２Ｏ（１０ｍＬ）で希釈し、ＤＣＭ（２×１０ｍＬ）で抽出し、合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物を分取ＨＰＬＣ（方法５）によって精製することで、標題化合物が（２０ｍｇ、０．０３９７ｍｍｏｌ、３７％の収率）白色の粉末として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 8.10 - 7.89 (m, 3H), 7.76 - 7.60 (m, 2H), 7.51 (t, J = 8.9 Hz, 1H), 7.13 - 7.05 (m, 1H), 6.91 - 6.83 (m, 1H), 4.56 (s, 2H), 3.99 - 3.83 (m, 2H), 3.03 - 2.94 (m, 1H), 2.49 - 2.39 (m, 1H), 2.34 - 2.15 (m, 2H), 2.04 - 1.82 (m, 3H), 1.57 - 1.43 (m, 1H), 0.92 (t, J = 7.1 Hz, 3H); M/Z: 493, 495, 497 [M+H]⁺, ESI⁺, RT = 3.12 (S4). [Example 47]
(Step 40.d): 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethylpiperidin-3-yl]acetamide

To a solution of (3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethyl-piperidin-3-amine trifluoroacetic acid (28% purity, 160 mg, 0.106 mmol) in DCM (5 mL) at 0° C. was added DIPEA (0.056 mL, 0.319 mmol) followed by a solution of 2-(4-chloro-3-fluoro-phenoxy)acetyl chloride (29 mg, 0.128 mmol, intermediate 19) in DCM (1 mL) and the mixture was stirred at room temperature for 5 h. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with DCM (2×10 mL) and the combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative HPLC (Method 5) to give the title compound (20 mg, 0.0397 mmol, 37% yield) as a white powder; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.10 - 7.89 (m, 3H), 7.76 - 7.60 (m, 2H), 7.51 (t, J = 8.9 Hz, 1H), 7.13 - 7.05 (m, 1H), 6.91 - 6.83 (m, 1H), 4.56 (s, 2H), 3.99 - 3.83 (m, 2H), 3.03 - 2.94 (m, 1H), 2.49 - 2.39 (m, 1H), 2.34 - 2.15 (m, 2H), 2.04 - 1.82 (m, 3H), 1.57 - 1.43 (m, 1H), 0.92 (t, J = 7.1 Hz, 3H); M/Z: 493, 495, 497 [M+H] ⁺ , ESI ⁺ , RT = 3.12 (S4).

Following general route 40, the example compounds in Table 15 were synthesized using the corresponding intermediates as exemplified by Example 47.

Scheme for Route 41

無水ＤＭＦ（１２ｍＬ）中の（１ｓ，３ｓ）－３－（トリフルオロメトキシ）シクロブタン－１－カルボン酸（３９７ｍｇ、２．１６ｍｍｏｌ、中間体５４）およびＤＩＰＥＡ（０．９４ｍＬ、５．３９ｍｍｏｌ）の溶液に、ＨＡＴＵ（８２０ｍｇ、２．１６ｍｍｏｌ）を添加し、混合物を室温で１０分間撹拌した。ＤＭＦ（７ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－（ヒドラジンカルボニル）ピペリジン－１－カルボキシレート（８００ｍｇ、１．８０ｍｍｏｌ、中間体２６）の溶液を添加し、混合物を室温で１２時間の間撹拌した。反応混合物をＨ_２Ｏ（５０ｍＬ）で希釈し、ＥｔＯＡｃ（２×５０ｍＬ）で抽出した。合わせた有機抽出物をブライン（２×５０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（８６％の純度、９７０ｍｇ、１．３７ｍｍｏｌ、７６％の収率）オフホワイトの固体として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 9.84 (s, 2H), 7.98 (d, J = 7.1 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.04 (dd, J = 11.4, 2.9 Hz, 1H), 6.82 (dd, J = 8.9, 1.8 Hz, 1H), 4.86 - 4.73 (m, 1H), 4.68 - 4.45 (m, 3H), 3.98 - 3.75 (m, 2H), 2.73 - 2.62 (m, 4H), 2.36 - 2.21 (m, 2H), 2.12 - 1.77 (m, 2H), 1.70 - 1.50 (m, 2H), 1.37 (s, 9H); M/Z: 609, 611 [M-Boc+H]⁺, ESI⁺, RT = 0.99 (S2). Step 41. a: tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{N'-[(1s,3s)-3-(trifluoromethoxy)cyclobutanecarbonyl]hydrazinecarbonyl}piperidine-1-carboxylate

To a solution of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (397 mg, 2.16 mmol, Intermediate 54) and DIPEA (0.94 mL, 5.39 mmol) in anhydrous DMF (12 mL) was added HATU (820 mg, 2.16 mmol) and the mixture was stirred at room temperature for 10 min. A solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(hydrazinecarbonyl)piperidine-1-carboxylate (800 mg, 1.80 mmol, Intermediate 26) in DMF (7 mL) was added and the mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with H ₂ O (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with brine (2×50 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (86% purity, 970 mg, 1.37 mmol, 76% yield) as an off-white solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.84 (s, 2H), 7.98 (d, J = 7.1 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.04 (dd, J = 11.4, 2.9 Hz, 1H), 6.82 (dd, J = 8.9, 1.8 Hz, 1H), 4.86 - 4.73 (m, 1H), 4.68 - 4.45 (m, 3H), 3.98 - 3.75 (m, M/Z: 609, 611 [M-Boc+H] ⁺ , ESI ⁺ , RT = 0.99 (S2).

ＡＣＮ（１０ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［［２－（４－クロロ－３－フルオロ－フェノキシ）アセチル］アミノ］－２－［［［（１Ｓ，３Ｓ）－３－（トリフルオロメトキシ）シクロブタンカルボニル］アミノ］カルバモイル］ピペリジン－１－カルボキシレート（８６％の純度、９７０ｍｇ、１．３７ｍｍｏｌ）、Ｋ_２ＣＯ_３（１１３２ｍｇ、８．１９ｍｍｏｌ）およびＴｓＣｌ（７８１ｍｇ、４．１０ｍｍｏｌ）の懸濁液を、８０℃で３時間の間撹拌した。反応混合物をＥｔＯＡｃ（１００ｍＬ）とＨ_２Ｏ（１００ｍＬ）との間で分配し、有機層を単離し、ブライン（１００ｍＬ）で洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（３１７ｍｇ、０．５２４ｍｍｏｌ、３８％の収率）オフホワイトの粉末として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 8.12 (d, J = 7.1 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.05 (dd, J = 11.4, 2.8 Hz, 1H), 6.82 (dd, J = 8.9, 1.9 Hz, 1H), 5.46 (s, 1H), 4.90 (p, J = 7.5 Hz, 1H), 4.64 - 4.54 (m, 2H), 3.90 (d, J = 12.2 Hz, 2H), 3.44 (tt, J = 9.8, 7.9 Hz, 1H), 3.35 - 3.29 (m, 1H), 2.96 (d, J = 7.8 Hz, 1H), 2.90 - 2.78 (m, 2H), 2.23 (ddq, J = 13.7, 9.7, 4.4 Hz, 1H), 2.05 (d, J = 11.4 Hz, 1H), 1.75 (m, J = 13.7, 10.1, 4.1 Hz, 1H), 1.64 (d, J = 13.3 Hz, 1H), 1.39 (s, 10H); M/Z: 493, 495 [M-Boc+H]⁺, ESI⁺, RT = 1.12 (S2). [Example 49]
(Step 41.b): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

A suspension of tert-butyl (2R,5S)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]-2-[[[(1S,3S)-3-(trifluoromethoxy)cyclobutanecarbonyl]amino]carbamoyl]piperidine-1-carboxylate (86% purity, 970 mg, 1.37 mmol), K ₂ CO ₃ (1132 mg, 8.19 mmol) and TsCl (781 mg, 4.10 mmol) in ACN (10 mL) was stirred for 3 h at 80° C. The reaction mixture was partitioned between EtOAc (100 mL) and H ₂ O (100 mL) and the organic layer was isolated, washed with brine (100 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (317 mg, 0.524 mmol, 38% yield) as an off-white powder; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.12 (d, J = 7.1 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.05 (dd, J = 11.4, 2.8 Hz, 1H), 6.82 (dd, J = 8.9, 1.9 Hz, 1H), 5.46 (s, 1H), 4.90 (p, J = 7.5 Hz, 1H), 4.64 - 4.54 (m, 2H), 3.90 (d, J = 12.2 Hz, 2H), 3.44 (tt, J = 9.8, 7.9 Hz, 1H), 3.35 - 3.29 (m, 1H), 2.96 (d, J = 7.8 Hz, 1H), 2.90 - 2.78 (m, 2H), 2.23 (ddq, J = 13.7, 9.7, M/Z: 493, 1.64 (d, J = 13.3 Hz, 1H), 1.39 (s, 10H); 495 [M-Boc+H] ⁺ , ESI ⁺ , RT = 1.12 (S2).

ＤＣＭ（１０ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－｛５－［（１ｓ，３ｓ）－３－（トリフルオロメトキシ）シクロブチル］－１，３，４－オキサジアゾール－２－イル｝ピペリジン－１－カルボキシレート（３１７ｍｇ、０．５２４ｍｍｏｌ、実施例４９）の溶液に、ＺｎＢｒ_２（７１４ｍｇ、３．１４ｍｍｏｌ）を添加し、混合物を室温でＮ_２下にて２０時間の間撹拌した。反応混合物を飽和ＮａＨＣＯ_３水溶液（１０ｍＬ）およびＤＣＭ（１０ｍＬ）中２０％のＩＰＡで希釈した。有機層を単離し、真空中で濃縮し、シリカゲル（ＤＣＭ中０～２０％のＭｅＯＨ）上のクロマトグラフィーによって精製することで、標題化合物が（２４０ｍｇ、０．４６７ｍｍｏｌ、８９％の収率）オフホワイトの粉末として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 7.97 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (m, J = 9.0, 2.9, 1.2 Hz, 1H), 4.96 - 4.85 (m, 1H), 4.52 (s, 2H), 3.92 - 3.82 (m, 1H), 3.79 - 3.63 (m, 1H), 3.48 - 3.37 (m, 1H), 3.00 (d, J = 12.3 Hz, 1H), 2.91 - 2.77 (m, 3H), 2.49 - 2.40 (m, 3H), 2.06 - 1.97 (m, 1H), 1.96 - 1.86 (m, 1H), 1.77 - 1.61 (m, 1H), 1.58 - 1.43 (m, 1H); M/Z: 493, 495 [M+H]⁺, ESI⁺, RT = 1.12 (S4). [Example 50]
(Step 41.c): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide

To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (317 mg, 0.524 mmol, Example 49) in DCM (10 mL) was added ZnBr ₂ (714 mg, 3.14 mmol) and the mixture was stirred at room temperature under N ₂ for 20 h. The reaction mixture was diluted with saturated aqueous NaHCO ₃ (10 mL) and 20% IPA in DCM (10 mL). The organic layer was isolated, concentrated in vacuo, and purified by chromatography on silica gel (0-20% MeOH in DCM) to give the title compound (240 mg, 0.467 mmol, 89% yield) as an off-white powder; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 7.97 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (m, J = 9.0, 2.9, 1.2 Hz, 1H), 4.96 - 4.85 (m, 1H), 4.52 (s, 2H), 3.92 - 3.82 (m, 1H), 3.79 - 3.63 (m, 1H), 3.48 - 3.37 (m, 1H), 3.00 (d, J = 12.3 Hz, 1H), 2.91 - 2.77 (m, 3H), 2.49 - 2.40 (m, 3H), 2.06 - 1.97 (m, 1H), 1.96 - 1.86 (m, 1H), 1.77 - 1.61 (m, 1H), 1.58 - 1.43 (m, 1H); M/Z: 493, 495 [M+H] ⁺ , ESI ⁺ , RT = 1.12 (S4).

Following general route 41, the example compounds in Table 16 were synthesized using the corresponding intermediates as exemplified by Example 50.

Scheme for Route 42

無水ＤＭＦ（２ｍＬ）中の１－（２，２，２－トリフルオロエチル）アゼチジン－３－カルボン酸（７４ｍｇ、０．４０５ｍｍｏｌ）の溶液に、ＨＡＴＵ（１８５ｍｇ、０．４８６ｍｍｏｌ）、続いてＤＩＰＥＡ（０．１４ｍＬ、０．８０９ｍｍｏｌ）を添加し、混合物を室温で１０分間撹拌した。ｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－（ヒドラジンカルボニル）ピペリジン－１－カルボキシレート（９０％の純度、２００ｍｇ、０．４０５ｍｍｏｌ、中間体２６）を添加し、混合物を室温で２０時間の間撹拌した。反応混合物をＨ_２Ｏ（５ｍＬ）で希釈し、ＥｔＯＡｃ（２×２０ｍＬ）で抽出した。合わせた有機抽出物をブライン（２０ｍＬ）で洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ、続いてＥｔＯＡｃ中０～２０％のＭｅＯＨ）上のクロマトグラフィーによって精製することで、標題化合物が（９０％の純度、２０６ｍｇ、０．３０３ｍｍｏｌ、７５％の収率）淡黄色のガムとして得られた；¹H NMR (400 MHz, DMSO-d₆) δ 9.81 (s, 2H), 8.05 - 7.93 (m, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.05 (dd, J = 11.4, 2.8 Hz, 1H), 6.83 (dd, J = 9.0, 1.8 Hz, 1H), 4.75 - 4.48 (m, 3H), 3.99 - 3.76 (m, 2H), 3.55 (t, J = 7.4 Hz, 2H), 3.17 (q, J = 10.2 Hz, 2H), 2.11 - 2.01 (m, 1H), 1.96 - 1.81 (m, 1H), 1.70 - 1.50 (m, 2H), 1.37 (s, 9H); M/Z: 610, 612 [M+H]⁺, ESI⁺, RT = 0.85 (S2). Step 42. a: tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{N'-[1-(2,2,2-trifluoroethyl)azetidine-3-carbonyl]hydrazinecarbonyl}piperidine-1-carboxylate

To a solution of 1-(2,2,2-trifluoroethyl)azetidine-3-carboxylic acid (74 mg, 0.405 mmol) in anhydrous DMF (2 mL) was added HATU (185 mg, 0.486 mmol) followed by DIPEA (0.14 mL, 0.809 mmol) and the mixture was stirred at room temperature for 10 min. tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(hydrazinecarbonyl)piperidine-1-carboxylate (90% purity, 200 mg, 0.405 mmol, intermediate 26) was added and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with H ₂ O (5 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO ₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane, followed by 0-20% MeOH in EtOAc) to give the title compound (90% purity, 206 mg, 0.303 mmol, 75% yield) as a pale yellow gum; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.81 (s, 2H), 8.05 - 7.93 (m, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.05 (dd, J = 11.4, 2.8 Hz, 1H), 6.83 (dd, J = 9.0, 1.8 Hz, 1H), 4.75 - 4.48 (m, 3H), 3.99 - 3.76 (m, 2H), 3.55 (t, J = 7.4 Hz, 2H), 3.17 (q, J = 10.2 Hz, 2H), 2.11 - 2.01 (m, 1H), 1.96 - 1.81 (m, 1H), 1.70 - 1.50 (m, 2H), 1.37 (s, 9H); M/Z: 610, 612 [M+H] ⁺ , ESI ⁺ , RT = 0.85 (S2).

ＡＣＮ（１．５３８４ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－｛Ｎ’－［１－（２，２，２－トリフルオロエチル）アゼチジン－３－カルボニル］ヒドラジンカルボニル｝ピペリジン－１－カルボキシレート（９０％の純度、２０６ｍｇ、０．３０３ｍｍｏｌ）、Ｋ_２ＣＯ_３（２５２ｍｇ、１．８２ｍｍｏｌ）およびＴｓＣｌ（０．０１２ｍＬ、０．９１０ｍｍｏｌ）の懸濁液を、８０℃で４５分間撹拌した。反応混合物をＨ_２Ｏ（５ｍＬ）で希釈し、ＥｔＯＡｃ（２×２０ｍＬ）で抽出した。合わせた有機抽出物をブライン（２０ｍＬ）で洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（１１０ｍｇ、０．１７９ｍｍｏｌ、５９％の収率）無色のガムとして得られた；¹H NMR (400 MHz, DMSO-d₆) δ 8.11 (d, J = 7.0 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.05 (dd, J = 11.4, 2.8 Hz, 1H), 6.87 - 6.79 (m, 1H), 5.48 (s, 1H), 4.65 - 4.49 (m, 2H), 4.00 - 3.94 (m, 1H), 3.92 (d, J = 11.6 Hz, 1H), 3.78 (t, J = 7.7 Hz, 2H), 3.56 (q, J = 6.8 Hz, 2H), 3.27 (dd, J = 20.3, 10.2 Hz, 2H), 3.09 - 2.93 (m, 1H), 2.31 - 2.17 (m, 1H), 2.11 - 2.00 (m, 1H), 1.76 (t, J = 13.7 Hz, 1H), 1.70 - 1.59 (m, 1H), 1.39 (s, 9H); M/Z: 592, 594 [M+H]⁺, ESI⁺, RT = 0.66 (S2) [Example 56]
(Step 42.b): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

A suspension of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{N'-[1-(2,2,2-trifluoroethyl)azetidine-3-carbonyl]hydrazinecarbonyl}piperidine-1-carboxylate (90% purity, 206 mg, 0.303 mmol), _K2CO3 (252 mg, 1.82 mmol) and TsCl (0.012 mL, 0.910 mmol) in ACN (1.5384 mL) was stirred at 80 _° C. for 45 min. The reaction mixture was diluted with _H2O (5 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (20 mL), dried over _MgSO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (110 mg, 0.179 mmol, 59% yield) as a colorless gum; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.11 (d, J = 7.0 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.05 (dd, J = 11.4, 2.8 Hz, 1H), 6.87 - 6.79 (m, 1H), 5.48 (s, 1H), 4.65 - 4.49 (m, 2H), 4.00 - 3.94 (m, 1H), 3.92 (d, J = 11.6 Hz, 1H), 3.78 (t, J = 7.7 Hz, 2H), 3.56 (q, J = 6.8 Hz, 2H), 3.27 (dd, J = 20.3, 10.2 Hz, 2H), 3.09 - 2.93 (m, 1H), 2.31 - 2.17 (m, 1H), 2.11 - 2.00 (m, 1H), 1.76 (t, J = 13.7 Hz, 1H), 1.70 - 1.59 (m, 1H), 1.39 (s, 9H); M/Z: 592, 594 [M+H] ⁺ , ESI ⁺ , RT = 0.66 (S2)

ＤＣＭ（２ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－｛５－［１－（２，２，２－トリフルオロエチル）アゼチジン－３－イル］－１，３，４－オキサジアゾール－２－イル｝ピペリジン－１－カルボキシレート（１１０ｍｇ、０．１７９ｍｍｏｌ、実施例５６）およびＴＦＡ（１３３μＬ、１．７９ｍｍｏｌ）の溶液を、室温で３時間の間撹拌した。反応混合物を飽和ＮａＨＣＯ_３水溶液（３ｍＬ）で希釈し、ＤＣＭ（２×５ｍＬ）で抽出した。合わせた有機抽出物を、相分離器を使用して乾燥させ、真空中で濃縮し、分取ＨＰＬＣ（方法３）によって精製することで、標題化合物が（２４ｍｇ、０．０４７８ｍｍｏｌ、２７％の収率）白色の固体として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 7.99 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.86 (ddd, J = 9.0, 2.8, 1.1 Hz, 1H), 4.53 (s, 2H), 4.01 - 3.92 (m, 1H), 3.88 (ddd, J = 10.4, 6.1, 2.9 Hz, 1H), 3.78 (t, J = 7.7 Hz, 2H), 3.76 - 3.66 (m, 1H), 3.56 (t, J = 6.9 Hz, 2H), 3.28 (q, J = 10.2 Hz, 2H), 3.00 (d, J = 11.5 Hz, 1H), 2.83 (q, J = 6.0 Hz, 1H), 2.48 - 2.42 (m, 1H), 2.06 - 1.97 (m, 1H), 1.95 - 1.87 (m, 1H), 1.75 - 1.64 (m, 1H), 1.52 (qd, J = 12.5, 3.9 Hz, 1H); M/Z: 492, 494 [M+H]⁺, ESI⁺, RT = 1.88 (S4). [Example 57]
(Step 42.c): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide

A solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (110 mg, 0.179 mmol, Example 56) and TFA (133 μL, 1.79 mmol) in DCM (2 mL) was stirred at room temperature for 3 h. The reaction mixture was diluted with saturated aqueous NaHCO ₃ (3 mL) and extracted with DCM (2 × 5 mL). The combined organic extracts were dried using a phase separator, concentrated in vacuo and purified by preparative HPLC (Method 3) to give the title compound (24 mg, 0.0478 mmol, 27% yield) as a white solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.99 (d, J = 8.1 Hz, 1H), 7.50 (t, J = 8.9 Hz, 1H), 7.08 (dd, J = 11.4, 2.8 Hz, 1H), 6.86 (ddd, J = 9.0, 2.8, 1.1 Hz, 1H), 4.53 (s, 2H), 4.01 - 3.92 (m, 1H), 3.88 (ddd, J = 10.4, 6.1, 2.9 Hz, 1H), 3.78 (t, J = 7.7 Hz, 2H), 3.76 - 3.66 (m, 1H), 3.56 (t, J = 6.9 Hz, 2H), 3.28 (q, J = 10.2 Hz, 2H), 3.00 (d, J = 11.5 Hz, 1H), 2.83 (q, J = 6.0 Hz, 1H), 2.48 - 2.42 (m, 1H), 2.06 - 1.97 (m, 1H), 1.95 - 1.87 (m, 1H), 1.75 - 1.64 (m, 1H), 1.52 (qd, J = 12.5, 3.9 Hz, 1H); M/Z: 492, 494 [M+H] ⁺ , ESI ⁺ , RT = 1.88 (S4).

Scheme for Route 43

ＴＨＦ（５ｍＬ）中の３－シクロプロポキシシクロブタン－１－カルボン酸（９０％の純度、１００ｍｇ、０．５７６ｍｍｏｌ、中間体５１）の溶液に、ＤＩＰＥＡ（３０２μＬ、１．７３ｍｍｏｌ）、Ｔ３Ｐ（５０％、１．０ｍＬ、１．７３ｍｍｏｌ）およびｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－（ヒドラジンカルボニル）ピペリジン－１－カルボキシレート（２５６ｍｇ、０．５７６ｍｍｏｌ、中間体２６）を添加し、混合物を室温で１８時間の間撹拌した。反応混合物をＨ_２Ｏ（３０ｍＬ）で希釈し、ＥｔＯＡｃ（２×５０ｍＬ）で抽出した。合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮することで、無色の固体が得られた。シリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによる精製で、標題化合物が（８５％の純度、１４３ｍｇ、０．２０８ｍｍｏｌ、３６％の収率）白色の固体として得られた；Ｍ／Ｚ：５８３、５８５［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝３．１８（Ｓ４）。 Step 43. a: tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[N'-(3-cyclopropoxycyclobutanecarbonyl)hydrazinecarbonyl]piperidine-1-carboxylate

To a solution of 3-cyclopropoxycyclobutane-1-carboxylic acid (90% purity, 100 mg, 0.576 mmol, Intermediate 51) in THF (5 mL) was added DIPEA (302 μL, 1.73 mmol), T3P (50%, 1.0 mL, 1.73 mmol) and tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(hydrazinecarbonyl)piperidine-1-carboxylate (256 mg, 0.576 mmol, Intermediate 26) and the mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo to give a colorless solid. Purification by chromatography on silica gel (0-100% EtOAc in heptane) afforded the title compound (85% purity, 143 mg, 0.208 mmol, 36% yield) as a white solid; M/Z: 583, 585 [M+H] ⁺ , ESI ⁺ , RT=3.18 (S4).

無水ＡＣＮ（１０ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－［Ｎ’－（３－シクロプロポキシシクロブタンカルボニル）ヒドラジンカルボニル］ピペリジン－１－カルボキシレート（８５％の純度、１４３ｍｇ、０．２０８ｍｍｏｌ）の溶液に、ＴｓＣｌ（７９ｍｇ、０．４１７ｍｍｏｌ）およびＫ_２ＣＯ_３（１４４ｍｇ、１．０４ｍｍｏｌ）を添加し、混合物を８０℃で５時間の間撹拌した。反応混合物をＨ_２Ｏ（３０ｍＬ）で希釈し、ＥｔＯＡｃ（２×５０ｍＬ）で抽出した。合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮することで、淡いオレンジ色の油状物が得られた。シリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによる精製で、標題化合物が（７０％の純度、１１１ｍｇ、０．１３８ｍｍｏｌ、６６％の収率）無色の固体として得られた；Ｍ／Ｚ：５６５、５６７［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝３．８５（Ｓ４）。 [Example 58]
(Step 43.b): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[N'-(3-cyclopropoxycyclobutanecarbonyl)hydrazinecarbonyl]piperidine-1-carboxylate (85% purity, 143 mg, 0.208 mmol) in anhydrous ACN (10 mL) was _added TsCl (79 mg, 0.417 mmol) and _K2CO3 (144 mg, 1.04 mmol) and the mixture was stirred at 80°C for 5 h. The reaction mixture was diluted with _H2O (30 mL) and extracted with EtOAc (2 x 50 _mL ). The combined organic extracts were dried over _Na2SO4 and concentrated in vacuo to give a pale orange oil. Purification by chromatography on silica gel (0-100% EtOAc in heptane) afforded the title compound (70% purity, 111 mg, 0.138 mmol, 66% yield) as a colorless solid; M/Z: 565, 567 [M+H] ⁺ , ESI ⁺ , RT=3.85 (S4).

ＤＣＭ（５ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－［５－（３－シクロプロポキシシクロブチル）－１，３，４－オキサジアゾール－２－イル］ピペリジン－１－カルボキシレート（７０％の純度、１１０ｍｇ、０．１３６ｍｍｏｌ、実施例５８）の溶液に、ＺｎＢｒ_２（９２ｍｇ、０．４０９ｍｍｏｌ）を添加し、結果として生じた混合物を室温で１６時間の間撹拌した。反応混合物をＮａＨＣＯ_３（３０ｍＬ）で希釈し、ＤＣＭ／ＩＰＡ（２：１、２×５０ｍＬ）で抽出し、合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物を分取ＨＰＬＣ（方法３）によって精製することで、標題化合物が（２６ｍｇ、０．０５５９ｍｍｏｌ、４１％の収率）白色の粉末として得られた；¹H NMR (400 MHz, methanol-d₄) δ 7.44 - 7.35 (m, 1H), 6.97 (dd, J = 11.0, 2.8 Hz, 1H), 6.86 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 4.55 (s, 2H), 4.27 - 4.15 (m, 1H), 4.05 - 3.92 (m, 2H), 3.41 - 3.34 (m, 2H), 3.25 - 3.19 (m, 1H), 2.81 - 2.60 (m, 3H), 2.40 - 2.26 (m, 2H), 2.23 - 2.06 (m, 2H), 1.94 - 1.81 (m, 1H), 1.73 - 1.59 (m, 1H), 0.60 - 0.42 (m, 4H); M/Z: 465, 467 [M+H]⁺, ESI⁺, RT = 1.97 (S4). [Example 59]
(Step 43.c): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide

To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (70% purity, 110 mg, 0.136 mmol, Example 58) in DCM (5 mL) was added ZnBr ₂ (92 mg, 0.409 mmol) and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with NaHCO ₃ (30 mL) and extracted with DCM/IPA (2:1, 2×50 mL) and the combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative HPLC (Method 3) to give the title compound (26 mg, 0.0559 mmol, 41% yield) as a white powder; ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.44 - 7.35 (m, 1H), 6.97 (dd, J = 11.0, 2.8 Hz, 1H), 6.86 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 4.55 (s, 2H), 4.27 - 4.15 (m, 1H), 4.05 - 3.92 (m, 2H), 3.41 - 3.34 (m, 2H), 3.25 - 3.19 (m, 1H), 2.81 - 2.60 (m, 3H), 2.40 - 2.26 (m, 2H), 2.23 - 2.06 (m, 2H), 1.94 - 1.81 (m, 1H), 1.73 - 1.59 (m, 1H), 0.60 - 0.42 (m, 4H); M/Z: 465, 467 [M+H] ⁺ , ESI ⁺ , RT = 1.97 (S4).

Following general route 43, the example compounds in Table 17 were synthesized using the corresponding intermediates as exemplified by Example 59.

Scheme for Route 44

無水ＴＨＦ（１ｍＬ）中の３，３，３－トリフルオロ－２－メチルプロパン－１－オール（３４ｍｇ、０．２６６ｍｍｏｌ）の懸濁液を０℃で、ＮａＨ（６０％、１１ｍｇ、０．２７１ｍｍｏｌ）で処理し、０℃でＮ_２下にて５分間撹拌した。無水ＴＨＦ（１ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－（５－メタンスルホニル－１，３，４－オキサジアゾール－２－イル）ピペリジン－１－カルボキシレート（７１ｍｇ、０．１３３ｍｍｏｌ、中間体５２）を添加し、混合物を室温で４５分間撹拌した。反応混合物を飽和ＮａＨＣＯ_３水溶液（１ｍＬ）で希釈し、ＥｔＯＡｃ（２×３ｍＬ）で抽出した。合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（７７ｍｇ、０．１３３ｍｍｏｌ）定量的収量で得られた。該粗材料を精製することなく前に進めた。 [Example 62]
(Step 44.a): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

A suspension of 3,3,3-trifluoro-2-methylpropan-1-ol (34 mg, 0.266 mmol) in anhydrous THF (1 mL) at 0° C. was treated with NaH (60%, 11 mg, 0.271 mmol) and stirred at 0° C. under N ₂ for 5 min. tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(5-methanesulfonyl-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (71 mg, 0.133 mmol, intermediate 52) in anhydrous THF (1 mL) was added and the mixture was stirred at room temperature for 45 min. The reaction mixture was diluted with saturated aqueous NaHCO ₃ (1 mL) and extracted with EtOAc (2×3 mL). The combined organic extracts were dried over _Na2SO4 and concentrated in _vacuo to give the title compound (77 mg, 0.133 mmol) in quantitative yield. The crude material was carried forward without purification.

ＤＣＭ（２ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－［５－（３，３，３－トリフルオロ－２－メチルプロポキシ）－１，３，４－オキサジアゾール－２－イル］ピペリジン－１－カルボキシレート（７７ｍｇ、０．１３３ｍｍｏｌ、実施例６２）の溶液に、ＺｎＢｒ_２（１８０ｍｇ、０．７９９ｍｍｏｌ）を添加し、混合物を室温で１７時間の間撹拌した。反応混合物を飽和ＮａＨＣＯ_３水溶液（１０ｍＬ）で希釈し、ＤＣＭ／ＩＰＡ（８：２、２×３ｍＬ）で抽出した。合わせた有機抽出物を、相分離器を使用して乾燥させ、真空中で濃縮し、分取ＨＰＬＣ（方法３）によって精製することで、標題化合物が（９４％の純度、７．０ｍｇ、０．０１４３ｍｍｏｌ、１１％の収率）白色の粉末として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 7.95 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.06 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.8, 1.1 Hz, 1H), 4.55 (d, J = 5.0 Hz, 2H), 4.52 (s, 2H), 3.78 - 3.73 (m, 1H), 3.73 - 3.65 (m, 1H), 3.13 - 3.01 (m, 1H), 3.00 - 2.92 (m, 1H), 2.83 - 2.76 (m, 1H), 2.46 - 2.39 (m, 1H), 1.99 - 1.86 (m, 2H), 1.70 - 1.59 (m, 1H), 1.53 - 1.45 (m, 1H), 1.19 (d, J = 7.1 Hz, 3H); M/Z: 481, 483 [M+H]⁺, ESI⁺, RT = 2.15 (S4). [Example 63]
(Step 44.b): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide

To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (77 mg, 0.133 mmol, Example 62) in DCM (2 mL) was added ZnBr ₂ (180 mg, 0.799 mmol) and the mixture was stirred at room temperature for 17 h. The reaction mixture was diluted with saturated aqueous NaHCO ₃ (10 mL) and extracted with DCM/IPA (8:2, 2×3 mL). The combined organic extracts were dried using a phase separator, concentrated in vacuo and purified by preparative HPLC (Method 3) to give the title compound (94% purity, 7.0 mg, 0.0143 mmol, 11% yield) as a white powder; ^1H NMR (500 MHz, DMSO- _d6 ) δ 7.95 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.06 (dd, J = 11.4, 2.8 Hz, 1H), 6.85 (ddd, J = 9.0, 2.8, 1.1 Hz, 1H), 4.55 (d, J = 5.0 Hz, 2H), 4.52 (s, 2H), 3.78 - 3.73 (m, 1H), 3.73 - 3.65 (m, 1H), 3.13 - 3.01 (m, 1H), 3.00 - 2.92 (m, 1H), 2.83 - 2.76 (m, 1H), 2.46 - 2.39 (m, 1H), 1.99 - 1.86 (m, 2H), 1.70 - 1.59 (m, 1H), 1.53 - 1.45 (m, 1H), 1.19 (d, J = 7.1 Hz, 3H); M/Z: 481, 483 [M+H] ⁺ , ESI ⁺ , RT = 2.15 (S4).

Following general route 44, the example compounds in Table 18 were synthesized using the corresponding intermediates as exemplified by Example 63.

Scheme for Route 45

無水ＴＨＦ（６ｍＬ）中の２－（トリフルオロメトキシ）エタノール（１３９ｍｇ、１．０７ｍｍｏｌ）の溶液に０℃で、ＮａＨ（６０％、４３ｍｇ、１．０７ｍｍｏｌ）を添加し、混合物を１０分間撹拌した。無水ＴＨＦ（６ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－２－（５－ブロモ－１，３，４－オキサジアゾール－２－イル）－５－［［２－（４－クロロ－３－フルオロ－フェノキシ）アセチル］アミノ］ピペリジン－１－カルボキシレート（５００ｍｇ、０．８９０ｍｍｏｌ、中間体３１）の溶液を添加し、混合物を室温で２時間の間撹拌した。反応混合物を水（１５ｍＬ）上に注ぎ、ＥｔＯＡｃ（３×１５ｍＬ）で抽出した。合わせた有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（８０％の純度、６２７ｍｇ、０．８６０ｍｍｏｌ、９７％の収率）黄色の油状物として得られた；¹H NMR (400 MHz, chloroform-d) δ 7.33 (t, J = 8.6 Hz, 1H), 6.91 - 6.61 (m, 3H), 5.48 (d, J = 25.4 Hz, 1H), 4.77 - 4.65 (m, 2H), 4.44 (dd, J = 14.2, 4.1 Hz, 2H), 4.38 - 4.29 (m, 2H), 4.22 - 4.01 (m, 2H), 3.17 (s, 1H), 2.27 - 2.06 (m, 1H), 1.91 (d, J = 26.1 Hz, 3H), 1.45 (s, 9H); M/Z: 483, 485 [M-Boc+H]⁺, ESI⁺, RT = 1.11 (S2). [Example 76]
(Step 45.a): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

To a solution of 2-(trifluoromethoxy)ethanol (139 mg, 1.07 mmol) in anhydrous THF (6 mL) at 0° C. was added NaH (60%, 43 mg, 1.07 mmol) and the mixture was stirred for 10 min. A solution of tert-butyl (2R,5S)-2-(5-bromo-1,3,4-oxadiazol-2-yl)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]piperidine-1-carboxylate (500 mg, 0.890 mmol, Intermediate 31) in anhydrous THF (6 mL) was added and the mixture was stirred at room temperature for 2 h. The reaction mixture was poured onto water (15 mL) and extracted with EtOAc (3×15 mL). The combined organic extracts were dried over _MgSO4 and concentrated in vacuo to give the title compound (80% purity, 627 mg, 0.860 mmol, 97% yield) as a yellow oil; ^1H NMR (400 MHz, chloroform-d) δ 7.33 (t, J = 8.6 Hz, 1H), 6.91 - 6.61 (m, 3H), 5.48 (d, J = 25.4 Hz, 1H), 4.77 - 4.65 (m, 2H), 4.44 (dd, J = 14.2, 4.1 Hz, 2H), 4.38 - 4.29 (m, 2H), 4.22 - 4.01 (m, 2H), 3.17 (s, 1H), 2.27 - 2.06 (m, 1H), 1.91 (d, J = 26.1 Hz, 3H), 1.45 (s, 9H); M/Z: 483, 485 [M-Boc+H] ⁺ , ESI ⁺ , RT = 1.11 (S2).

ＤＣＭ（９ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－｛５－［２－（トリフルオロメトキシ）エトキシ］－１，３，４－オキサジアゾール－２－イル｝ピペリジン－１－カルボキシレート（８０％の純度、６２７ｍｇ、０．８６０ｍｍｏｌ、実施例７６）の溶液に、ＺｎＢｒ_２（５８１ｍｇ、２．５８ｍｍｏｌ）を添加し、混合物を室温で１２時間の間撹拌した。反応物をＨ_２Ｏ（２０ｍＬ）上に注ぎ、ＤＣＭ（３×２０ｍＬ）中１０％のＩＰＡで抽出した。合わせた有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中で濃縮した。残留物を分取ＨＰＬＣ（方法４）によって精製することで、標題化合物が（１９４ｍｇ、０．３９４ｍｍｏｌ、４６％の収率）白色の固体として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 7.99 (d, J = 8.1 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.06 (dd, J = 11.4, 2.8 Hz, 1H), 6.84 (m, J = 9.0, 2.8, 1.1 Hz, 1H), 4.70 - 4.65 (m, 2H), 4.51 (s, 2H), 4.49 - 4.44 (m, 2H), 3.79 - 3.73 (m, 1H), 3.73 - 3.65 (m, 1H), 2.96 (dd, J = 11.5, 3.2 Hz, 1H), 2.79 (s, 1H), 2.47 - 2.38 (m, 1H), 1.99 - 1.84 (m, 2H), 1.69 - 1.58 (m, 1H), 1.54 - 1.44 (m, 1H); M/Z: 483, 485 [M+H]⁺, ESI⁺, RT = 2.19 (S4). [Example 77]
(Step 45.b): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide

To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (80% purity, 627 mg, 0.860 mmol, Example 76) in DCM (9 mL) was added ZnBr ₂ (581 mg, 2.58 mmol) and the mixture was stirred at room temperature for 12 h. The reaction was poured onto H ₂ O (20 mL) and extracted with 10% IPA in DCM (3×20 mL). The combined organic extracts were dried over MgSO ₄ and concentrated in vacuo. The residue was purified by preparative HPLC (Method 4) to give the title compound (194 mg, 0.394 mmol, 46% yield) as a white solid; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.99 (d, J = 8.1 Hz, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.06 (dd, J = 11.4, 2.8 Hz, 1H), 6.84 (m, J = 9.0, 2.8, 1.1 Hz, 1H), 4.70 - 4.65 (m, 2H), 4.51 (s, 2H), 4.49 - 4.44 (m, 2H), 3.79 - 3.73 (m, 1H), 3.73 - 3.65 (m, 1H), 2.96 (dd, J = 11.5, 3.2 Hz, 1H), 2.79 (s, 1H), 2.47 - 2.38 (m, 1H), 1.99 - 1.84 (m, 2H), 1.69 - 1.58 (m, 1H), 1.54 - 1.44 (m, 1H); M/Z: 483, 485 [M+H] ⁺ , ESI ⁺ , RT = 2.19 (S4).

Following general route 45, the example compounds in Table 19 were synthesized using the corresponding intermediates as exemplified by Example 77.

Scheme for Route 46

ＤＣＭ（１０ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－２－（５－ブロモ－１，３，４－オキサジアゾール－２－イル）－５－［２－（３，４－ジクロロフェノキシ）アセトアミド］ピペリジン－１－カルボキシレート（４００ｍｇ、０．７１２ｍｍｏｌ、中間体３２）の溶液に、ＺｎＢｒ_２（６４２ｍｇ、２．８５ｍｍｏｌ）を添加し、混合物を室温で６時間の間撹拌した。さらなる一分量のＺｎＢｒ_２（６４２ｍｇ、２．８５ｍｍｏｌ）を添加し、混合物を室温で４８時間の間撹拌した。反応混合物をＨ_２Ｏ（５０ｍＬ）で希釈し、ＤＣＭ／ＩＰＡ（２：１、３×５０ｍＬ）で抽出した。合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（８０％の純度、２６９ｍｇ、０．４７８ｍｍｏｌ、６７％の収率）淡黄色の粉末として得られた；Ｍ／Ｚ：４５１、４５３、４５５［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝０．７７（Ｓ２）。 Step 46. a: N-[(3S,6R)-6-(5-bromo-1,3,4-oxadiazol-2-yl)piperidin-3-yl]-2-(3,4-dichlorophenoxy)acetamide

To a solution of tert-butyl (2R,5S)-2-(5-bromo-1,3,4-oxadiazol-2-yl)-5-[2-(3,4-dichlorophenoxy)acetamido]piperidine-1-carboxylate (400 mg, 0.712 mmol, intermediate 32) in DCM (10 mL) was added ZnBr ₂ (642 mg, 2.85 mmol) and the mixture was stirred at room temperature for 6 h. An additional portion of ZnBr ₂ (642 mg, 2.85 mmol) was added and the mixture was stirred at room temperature for 48 h. The reaction mixture was diluted with H ₂ O (50 mL) and extracted with DCM/IPA (2:1, 3×50 mL). The combined organic extracts were dried over _Na2SO4 and concentrated in vacuo to give the title compound (80% purity, 269 mg, 0.478 mmol, 67% yield) as a pale yellow powder; M/ _Z : 451, 453, 455 [M+H] ⁺ , ESI ⁺ , RT=0.77 (S2).

無水ＴＨＦ（３ｍＬ）中の２－（トリフルオロメトキシ）エタノール（４３μＬ、０．４２７ｍｍｏｌ）の溶液に０℃で、ＮａＨ（６０％、１７ｍｇ、０．４２７ｍｍｏｌ）を添加し、溶液を室温で５分間撹拌した。Ｎ－［（３Ｓ，６Ｒ）－６－（５－ブロモ－１，３，４－オキサジアゾール－２－イル）ピペリジン－３－イル］－２－（３，４－ジクロロフェノキシ）アセトアミド（８０％の純度、２００ｍｇ、０．３５５ｍｍｏｌ）を添加し、結果として生じた混合物を室温で１時間の間撹拌した。反応混合物をＨ_２Ｏ（３０ｍＬ）で希釈し、ＥｔＯＡｃ（２×５０ｍＬ）で抽出した。合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮することで、オレンジ色の油状物が得られた。残留物をシリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィー、続いて分取ＨＰＬＣ（方法３）によって精製することで、標題化合物が（１７ｍｇ、０．０３３７ｍｍｏｌ、１０％の収率）白色の粉末として得られた；¹H NMR (400 MHz, methanol-d₄) δ 7.46 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 2.9 Hz, 1H), 6.98 (dd, J = 8.9, 2.9 Hz, 1H), 4.74 - 4.70 (m, 2H), 4.55 (s, 2H), 4.46 - 4.42 (m, 2H), 4.01 - 3.93 (m, 1H), 3.92 - 3.87 (m, 1H), 3.24 - 3.18 (m, 1H), 2.66 - 2.57 (m, 1H), 2.19 - 2.06 (m, 2H), 1.91 - 1.80 (m, 1H), 1.70 - 1.58 (m, 1H); M/Z: 499, 501, 503 [M+H]⁺, ESI⁺, RT = 2.30 (S4). [Example 85]
(Step 46.b): 2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide

To a solution of 2-(trifluoromethoxy)ethanol (43 μL, 0.427 mmol) in anhydrous THF (3 mL) at 0° C. was added NaH (60%, 17 mg, 0.427 mmol) and the solution was stirred at room temperature for 5 min. N-[(3S,6R)-6-(5-bromo-1,3,4-oxadiazol-2-yl)piperidin-3-yl]-2-(3,4-dichlorophenoxy)acetamide (80% purity, 200 mg, 0.355 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with H ₂ O (30 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo to give an orange oil. The residue was purified by chromatography on silica gel (0-100% EtOAc in heptane) followed by preparative HPLC (Method 3) to give the title compound (17 mg, 0.0337 mmol, 10% yield) as a white powder; ¹ H NMR (400 MHz, methanol-d ₄ ) δ 7.46 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 2.9 Hz, 1H), 6.98 (dd, J = 8.9, 2.9 Hz, 1H), 4.74 - 4.70 (m, 2H), 4.55 (s, 2H), 4.46 - 4.42 (m, 2H), 4.01 - 3.93 (m, 1H), 3.92 - 3.87 (m, 1H), 3.24 – 3.18 (m, 1H), 2.66 – 2.57 (m, 1H), 2.19 – 2.06 (m, 2H), 1.91 – 1.80 (m, 1H), 1.70 – ^1.58 (m, 1H); ESI ⁺ , RT = 2.30 (S4).

Following general route 46, the example compounds in Table 20 were synthesized using the corresponding intermediates as exemplified by Example 85.

Scheme for Route 47

無水ＤＭＦ（１ｍＬ）中の３－（トリフルオロメチル）アゼチジン塩酸塩（６０ｍｇ、０．３７１ｍｍｏｌ）の溶液に、ＤＩＰＥＡ（０．１６ｍＬ、０．９２７ｍｍｏｌ）、続いて無水ＤＭＦ（１ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－２－（５－ブロモ－１，３，４－オキサジアゾール－２－イル）－５－［［２－（４－クロロ－３－フルオロ－フェノキシ）アセチル］アミノ］ピペリジン－１－カルボキシレート（１００ｍｇ、０．１８５ｍｍｏｌ、中間体３１）の溶液を添加し、混合物を１００℃で２時間の間撹拌した。反応混合物をＨ_２Ｏ（１０ｍＬ）で希釈し、ＥｔＯＡｃ（３×１０ｍＬ）で抽出した。合わせた有機抽出物をブライン（２×３０ｍＬ）で洗浄し、ＭｇＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（８７％の純度、１１７ｍｇ、０．１７６ｍｍｏｌ、９５％の収率）茶色の油状物として得られた；Ｍ／Ｚ：４７８、４８０［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝１．１３（Ｓ２）。 [Example 89]
(Step 47.a): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[3-(trifluoromethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate

To a solution of 3-(trifluoromethyl)azetidine hydrochloride (60 mg, 0.371 mmol) in anhydrous DMF (1 mL) was added DIPEA (0.16 mL, 0.927 mmol), followed by a solution of tert-butyl (2R,5S)-2-(5-bromo-1,3,4-oxadiazol-2-yl)-5-[[2-(4-chloro-3-fluoro-phenoxy)acetyl]amino]piperidine-1-carboxylate (100 mg, 0.185 mmol, Intermediate 31) in anhydrous DMF (1 mL) and the mixture was stirred for 2 h at 100° C. The reaction mixture was diluted with H ₂ O (10 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were washed with brine (2×30 mL), dried over _MgSO4 , and concentrated in vacuo to give the title compound (87% purity, 117 mg, 0.176 mmol, 95% yield) as a brown oil; M/Z: 478, 480 [M+H] ⁺ , ESI ⁺ , RT=1.13 (S2).

ＤＣＭ（２ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－｛５－［３－（トリフルオロメチル）アゼチジン－１－イル］－１，３，４－オキサジアゾール－２－イル｝ピペリジン－１－カルボキシレート（８７％の純度、１１５ｍｇ、０．１７３ｍｍｏｌ）の溶液に、ＺｎＢｒ_２（１１７ｍｇ、０．５１９ｍｍｏｌ）を添加し、混合物を室温で２０時間の間撹拌した。反応混合物を飽和ＮａＨＣＯ_３水溶液（３ｍＬ）で希釈し、ＤＣＭ：ＩＰＡ（８０：２０、３×３ｍＬ）で抽出した。合わせた有機抽出物を、相分離器を使用して乾燥させ、真空中で濃縮した。残留物を分取ＨＰＬＣ（方法４）によって精製することで、標題化合物が（３７ｍｇ、０．０７７４ｍｍｏｌ、４５％の収率）白色の粉末として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 7.96 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.07 (m, 1H), 6.87 - 6.82 (m, 1H), 4.51 (s, 2H), 4.37 - 4.30 (m, 2H), 4.10 - 4.04 (m, 2H), 3.85 - 3.75 (m, 1H), 3.75 - 3.64 (m, 2H), 3.01 - 2.94 (m, 1H), 2.75 - 2.67 (m, 1H), 2.47 - 2.37 (m, 1H), 1.97 - 1.85 (m, 2H), 1.69 - 1.58 (m, 1H), 1.54 - 1.42 (m, 1H); M/Z: 480, 482 [M+H]⁺, ESI⁺, RT = 1.97 (S4). [Example 90]
(Step 47.b): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide

To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[3-(trifluoromethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate (87% purity, 115 mg, 0.173 mmol) in DCM (2 mL) was added ZnBr ₂ (117 mg, 0.519 mmol) and the mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with saturated aqueous NaHCO ₃ (3 mL) and extracted with DCM:IPA (80:20, 3×3 mL). The combined organic extracts were dried using a phase separator and concentrated in vacuo. The residue was purified by preparative HPLC (Method 4) to give the title compound (37 mg, 0.0774 mmol, 45% yield) as a white powder; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 7.96 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.07 (m, 1H), 6.87 - 6.82 (m, 1H), 4.51 (s, 2H), 4.37 - 4.30 (m, 2H), 4.10 - 4.04 (m, 2H), 3.85 - 3.75 (m, 1H), 3.75 - 3.64 (m, 2H), 3.01 - 2.94 (m, 1H), 2.75 - 2.67 (m, 1H), 2.47 - 2.37 (m, 1H), 1.97 - 1.85 (m, 2H), 1.69 - 1.58 (m, 1H), 1.54 - 1.42 (m, 1H); M/Z: 480, 482 [M+H] ⁺ , ESI ⁺ , RT = 1.97 (S4).

Following general route 47, the example compounds in Table 21 were synthesized using the corresponding intermediates as exemplified by Example 90.

Scheme for Route 48

無水ＤＭＦ（２２ｍＬ）中の（２Ｒ，５Ｓ）－１－［（ｔｅｒｔ－ブトキシ）カルボニル］－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］ピペリジン－２－カルボン酸（１．８６ｇ、４．３２ｍｍｏｌ、中間体２２）、ＮＨ_４Ｃｌ（２５３ｍｇ、４．７３ｍｍｏｌ）およびＤＩＰＥＡ（３．１ｍＬ、１７．７ｍｍｏｌ）の溶液に０℃で、ＨＡＴＵ（１．８０ｇ、４．７３ｍｍｏｌ）を添加し、混合物を室温で４時間の間撹拌した。反応混合物をＥｔＯＡｃ（１００ｍＬ）で希釈し、ブライン（３×５０ｍＬ）で洗浄した。合わせた有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（８０％の純度、２．３６ｇ、４．３９ｍｍｏｌ）定量的収量で無色の結晶として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 7.99 - 7.93 (m, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.32 (s, 1H), 7.08 - 6.99 (m, 2H), 6.81 (dd, J = 8.9, 1.9 Hz, 1H), 4.63 - 4.37 (m, 3H), 3.97 - 3.74 (m, 2H), 3.27 - 3.08 (m, 1H), 1.98 - 1.81 (m, 2H), 1.60 - 1.47 (m, 2H), 1.36 (s, 9H); M/Z: 330, 332 [M+H]⁺, ESI⁺, RT = 0.88 (S2). Step 48. a: tert-Butyl (2R,5S)-2-carbamoyl-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylate

To a solution of (2R,5S)-1-[(tert-butoxy)carbonyl]-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-2-carboxylic acid (1.86 g, 4.32 mmol, intermediate 22), NH ₄ Cl (253 mg, 4.73 mmol) and DIPEA (3.1 mL, 17.7 mmol) in anhydrous DMF (22 mL) at 0° C. was added HATU (1.80 g, 4.73 mmol) and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine (3×50 mL). The combined organic extracts were dried over _MgSO4 and concentrated in vacuo to give the title compound (80% purity, 2.36 g, 4.39 mmol) as colorless crystals in quantitative yield; ^1H NMR (500 MHz, DMSO- _d6 ) δ 7.99 - 7.93 (m, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.32 (s, 1H), 7.08 - 6.99 (m, 2H), 6.81 (dd, J = 8.9, 1.9 Hz, 1H), 4.63 - 4.37 (m, 3H), 3.97 - 3.74 (m, 2H), 3.27 - 3.08 (m, 1H), 1.98 - 1.81 (m, 2H), 1.60 - 1.47 (m, 2H), 1.36 (s, 9H); M/Z: 330, 332 [M+H] ⁺ , ESI ⁺ , RT = 0.88 (S2).

無水ＤＣＭ（４０ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－２－カルバモイル－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］ピペリジン－１－カルボキシレート（８０％の純度、２．１７ｇ、４．０４ｍｍｏｌ）およびＥｔ_３Ｎ（２．６ｍＬ、１８．７ｍｍｏｌ）の溶液に０℃で、ＴＦＡＡ（１．２ｍＬ、８．２７ｍｍｏｌ）を添加し、溶液を室温で２時間の間撹拌した。反応混合物を０℃に冷却し、Ｈ_２Ｏ（２０ｍＬ）でクエンチした。溶液をＤＣＭ（５０ｍＬ）で希釈し、飽和ＮａＨＣＯ_３水溶液（２０ｍＬ）で洗浄した。有機層を、相分離器を使用して乾燥させ、真空中で濃縮し、シリカゲル（ヘプタン中０～５０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（０．９４ｇ、２．２２ｍｍｏｌ、５５％の収率）白色の粉末として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 8.06 (d, J = 6.9 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.02 (dd, J = 11.4, 2.8 Hz, 1H), 6.80 (dd, J = 8.9, 2.0 Hz, 1H), 5.37 - 5.27 (m, 1H), 4.61 - 4.50 (m, 2H), 4.03 - 3.90 (m, 2H), 3.07 - 2.92 (m, 1H), 2.17 - 2.04 (m, 1H), 1.84 - 1.68 (m, 3H), 1.39 (s, 9H); M/Z: 429, 431 [M+NH₄]⁺, ESI⁺, RT = 3.69 (S6). Step 48. b: tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-cyanopiperidine-1-carboxylate

To a solution of tert-butyl (2R,5S)-2-carbamoyl-5-[2-(4-chloro-3-fluorophenoxy)acetamido]piperidine-1-carboxylate (80% purity, 2.17 g, 4.04 mmol) and Et ₃ N (2.6 mL, 18.7 mmol) in anhydrous DCM (40 mL) at 0° C., TFAA (1.2 mL, 8.27 mmol) was added and the solution was stirred at room temperature for 2 h. The reaction mixture was cooled to 0° C. and quenched with H ₂ O (20 mL). The solution was diluted with DCM (50 mL) and washed with saturated aqueous NaHCO ₃ (20 mL). The organic layer was dried using a phase separator, concentrated in vacuo, and purified by chromatography on silica gel (0-50% EtOAc in heptane) to give the title compound (0.94 g, 2.22 mmol, 55% yield) as a white powder; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 8.06 (d, J = 6.9 Hz, 1H), 7.47 (t, J = 8.9 Hz, 1H), 7.02 (dd, J = 11.4, 2.8 Hz, 1H), 6.80 (dd, J = 8.9, 2.0 Hz, 1H), 5.37 - 5.27 (m, 1H), 4.61 - 4.50 (m, 2H), 4.03 - 3.90 (m, 2H), 3.07 - 2.92 (m, 1H), 2.17 - 2.04 (m, 1H), 1.84 - 1.68 (m, 3H), 1.39 (s, 9H); M/Z: 429, 431 [M+NH ₄ ] ⁺ , ESI ⁺ , RT = 3.69 (S6).

ＭｅＯＨ（６ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－シアノピペリジン－１－カルボキシレート（５００ｍｇ、１．２１ｍｍｏｌ）の溶液に０℃で、ヒドロキシルアミン塩酸塩（１：１）（１２５ｍｇ、１．８０ｍｍｏｌ）およびＮａＨＣＯ_３（２２５ｍｇ、２．６８ｍｍｏｌ）を添加し、反応混合物を室温で４０時間の間撹拌した。結果として得られた懸濁液を真空下で濾過し、ＭｅＯＨで洗浄して、濾液を真空中で濃縮することで、標題化合物が（６９％の純度、６２０ｍｇ、０．９６２ｍｍｏｌ、７９％の収率）白色の粉末として得られた；¹H NMR (500 MHz, DMSO-d₆) δ 8.01 - 7.90 (m, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.05 (dd, J = 11.3, 2.9 Hz, 1H), 6.82 (ddd, J = 9.0, 2.8, 0.9 Hz, 1H), 5.22 (s, 1H), 4.67 (s, 1H), 4.62 - 4.51 (m, 2H), 3.95 - 3.78 (m, 2H), 3.19 - 3.11 (m, 1H), 2.00 - 1.82 (m, 2H), 1.75 (d, J = 16.9 Hz, 1H), 1.59 - 1.47 (m, 1H), 1.37 (s, 9H); M/Z: 345, 347 [M-Boc+H]⁺, ESI⁺, RT = 0.78 (S2). Step 48. c: tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(N-hydroxycarbamimidoyl)piperidine-1-carboxylate

To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-cyanopiperidine-1-carboxylate (500 mg, 1.21 mmol) in MeOH (6 mL) at 0° C. was added hydroxylamine hydrochloride (1:1) (125 mg, 1.80 mmol) and NaHCO ₃ (225 mg, 2.68 mmol) and the reaction mixture was stirred at room temperature for 40 h. The resulting suspension was filtered under vacuum, washed with MeOH, and the filtrate was concentrated in vacuo to give the title compound (69% purity, 620 mg, 0.962 mmol, 79% yield) as a white powder; ^1H NMR (500 MHz, DMSO- _d6 ) δ 8.01 - 7.90 (m, 1H), 7.48 (t, J = 8.9 Hz, 1H), 7.05 (dd, J = 11.3, 2.9 Hz, 1H), 6.82 (ddd, J = 9.0, 2.8, 0.9 Hz, 1H), 5.22 (s, 1H), 4.67 (s, 1H), 4.62 - 4.51 (m, 2H), 3.95 - 3.78 (m, 2H), 3.19 - M/Z: 345, 347 [M-Boc+H] ⁺ , ESI ⁺ , RT = 0.78 (S2).

無水ＤＭＦ（２．５ｍＬ）中の（１ｓ，３ｓ）－３－（トリフルオロメトキシ）シクロブタン－１－カルボン酸（９０ｍｇ、０．４８９ｍｍｏｌ、中間体５４）の溶液に、Ｅｔ_３Ｎ（２０２μＬ、１．４５ｍｍｏｌ）、続いてＨＡＴＵ（２００ｍｇ、０．５２６ｍｍｏｌ）を添加し、室温で１０分間撹拌した。ｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－（Ｎ－ヒドロキシカルバミミドイル）ピペリジン－１－カルボキシレート（６９％の純度、３１０ｍｇ、０．４８１ｍｍｏｌ）を添加し、結果として生じた混合物を室温で１７時間の間撹拌した。反応混合物をＥｔＯＡｃ（３０ｍＬ）で希釈し、ブライン（３×２０ｍＬ）で洗浄した。合わせた有機抽出物をＭｇＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（５９％の純度、３６７ｍｇ、０．３５４ｍｍｏｌ、７４％の収率）オレンジ色の油状物として得られた；Ｍ／Ｚ：５１１、５１３［Ｍ－Ｂｏｃ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝１．１２（Ｓ２）。 Step 48. d: tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{N-[(1s,3s)-3-(trifluoromethoxy)cyclobutanecarbonyloxy]carbamimidoyl}piperidine-1-carboxylate

To a solution of (1s,3s)-3-(trifluoromethoxy)cyclobutane-1-carboxylic acid (90 mg, 0.489 mmol, intermediate 54) in anhydrous DMF (2.5 mL) was added Et ₃ N (202 μL, 1.45 mmol) followed by HATU (200 mg, 0.526 mmol) and stirred at room temperature for 10 min. tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-(N-hydroxycarbamimidoyl)piperidine-1-carboxylate (69% purity, 310 mg, 0.481 mmol) was added and the resulting mixture was stirred at room temperature for 17 h. The reaction mixture was diluted with EtOAc (30 mL) and washed with brine (3×20 mL). The combined organic extracts were dried over _MgSO4 and concentrated in vacuo to give the title compound (59% purity, 367 mg, 0.354 mmol, 74% yield) as an orange oil; M/Z: 511, 513 [M-Boc+H] ⁺ , ESI ⁺ , RT=1.12 (S2).

ピリジン（３．５ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－｛Ｎ－［（１ｓ，３ｓ）－３－（トリフルオロメトキシ）シクロブタンカルボニルオキシ］カルバミミドイル｝ピペリジン－１－カルボキシレート（５９％の純度、３６７ｍｇ、０．３５４ｍｍｏｌ）の溶液を、１１５℃で１７時間の間撹拌した。反応混合物を真空中で濃縮し、シリカゲル（ヘプタン中０～１００％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（９１％の純度、１７２ｍｇ、０．２６４ｍｍｏｌ、７４％の収率）無色の油状物として得られた；Ｍ／Ｚ：５９３、５９５［Ｍ＋Ｈ］^＋、ＥＳＩ^＋、ＲＴ＝１．２０（Ｓ２）。 [Example 97]
(Step 48.e): tert-Butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxylate

A solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{N-[(1s,3s)-3-(trifluoromethoxy)cyclobutanecarbonyloxy]carbamimidoyl}piperidine-1-carboxylate (59% purity, 367 mg, 0.354 mmol) in pyridine (3.5 mL) was stirred for 17 h at 115° C. The reaction mixture was concentrated in vacuo and purified by chromatography on silica gel (0-100% EtOAc in heptane) to give the title compound (91% purity, 172 mg, 0.264 mmol, 74% yield) as a colorless oil; M/Z: 593, 595 [M+H] ⁺ , ESI ⁺ , RT=1.20 (S2).

無水ＤＣＭ（１．５ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－［２－（４－クロロ－３－フルオロフェノキシ）アセトアミド］－２－｛５－［（１ｓ，３ｓ）－３－（トリフルオロメトキシ）シクロブチル］－１，２，４－オキサジアゾール－３－イル｝ピペリジン－１－カルボキシレート（９１％の純度、１５２ｍｇ、０．２３３ｍｍｏｌ、実施例９７）の溶液に、ＺｎＢｒ_２（２１０ｍｇ、０．９２４ｍｍｏｌ）を添加し、結果として生じた混合物を室温でＮ_２下にて１７時間の間撹拌した。反応混合物を飽和ＮａＨＣＯ_３水溶液（２０ｍＬ）で希釈し、８０：２０のＤＣＭ／ＩＰＡ（３×５０ｍＬ）で抽出した。合わせた有機抽出物を、相分離器を使用して乾燥させ、真空中で濃縮し、分取ＨＰＬＣ（方法４）によって精製することで、標題化合物が（６８ｍｇ、０．１３８ｍｍｏｌ、５９％の収率）白色の固体として得られた；¹H NMR (400 MHz, chloroform-d) δ 7.33 (t, J = 8.6 Hz, 1H), 6.78 (dd, J = 10.3, 2.8 Hz, 1H), 6.70 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 6.60 - 6.53 (m, 1H), 4.71 (p, J = 7.6 Hz, 1H), 4.46 (s, 2H), 4.10 - 4.00 (m, 1H), 3.94 (dd, J = 9.1, 3.0 Hz, 1H), 3.40 - 3.28 (m, 2H), 2.94 - 2.85 (m, 2H), 2.78 - 2.66 (m, 2H), 2.64 - 2.57 (m, 1H), 2.18 - 2.01 (m, 3H), 1.94 - 1.82 (m, 1H), 1.63 - 1.57 (m, 1H); M/Z: 493, 495 [M+H]⁺, ESI⁺, RT = 2.32 (S4). [Example 98]
(Step 48.f): 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-3-yl}piperidin-3-yl]acetamide

To a solution of tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxylate (91% purity, 152 mg, 0.233 mmol, Example 97) in anhydrous DCM (1.5 mL) was added ZnBr ₂ (210 mg, 0.924 mmol) and the resulting mixture was stirred at room temperature under N ₂ for 17 h. The reaction mixture was diluted with saturated aqueous NaHCO ₃ (20 mL) and extracted with 80:20 DCM/IPA (3 x 50 mL). The combined organic extracts were dried using a phase separator, concentrated in vacuo and purified by preparative HPLC (Method 4) to give the title compound (68 mg, 0.138 mmol, 59% yield) as a white solid; ¹ H NMR (400 MHz, chloroform-d) δ 7.33 (t, J = 8.6 Hz, 1H), 6.78 (dd, J = 10.3, 2.8 Hz, 1H), 6.70 (ddd, J = 8.9, 2.8, 1.2 Hz, 1H), 6.60 - 6.53 (m, 1H), 4.71 (p, J = 7.6 Hz, 1H), 4.46 (s, 2H), 4.10 - 4.00 (m, 1H), 3.94 (dd, J = 9.1, 3.0 Hz, 1H), 3.40 - 3.28 (m, 2H), 2.94 - 2.85 (m, 2H), 2.78 - 2.66 (m, 2H), 2.64 - 2.57 (m, 1H), 2.18 - 2.01 (m, 3H), 1.94 - 1.82 (m, 1H), 1.63 - 1.57 (m, 1H); M/Z: 493, 495 [M+H] ⁺ , ESI ⁺ , RT = 2.32 (S4).

Scheme for Route 49

無水ＴＨＦ（２０ｍＬ）中の２－［（６－クロロ－５－フルオロピリジン－３－イル）オキシ］酢酸（４００ｍｇ、１．９５ｍｍｏｌ、中間体１２）の溶液に０℃で、クロロギ酸イソブチル（０．２４ｍＬ、１．８５ｍｍｏｌ）、続いてＮＭＭ（０．２１ｍＬ、１．９５ｍｍｏｌ）を添加した。混合物を１５分間撹拌した後に、１－ｔｅｒｔ－ブチル２－エチル（２Ｒ，５Ｓ）－５－アミノアミノピペリジン－１，２－ジカルボキシレート（５３０ｍｇ、１．９５ｍｍｏｌ、中間体３）を添加し、結果として生じた混合物を室温で１時間の間撹拌した。反応混合物を０℃に冷却し、Ｈ_２Ｏ（０．５ｍＬ）でクエンチし、真空中で濃縮した。残留物をＥｔＯＡｃ（１０ｍＬ）とＨ_２Ｏ（１０ｍＬ）との間で分配した。有機層を単離し、飽和ＮａＨＣＯ_３水溶液（１０ｍＬ）およびブライン（１０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（９０％の純度、８０５ｍｇ、１．５８ｍｍｏｌ、８１％の収率）オフホワイトの固体として得られた；¹H NMR (400 MHz, chloroform-d) δ 7.98 (d, J = 2.6 Hz, 1H), 7.12 (dd, J = 8.8, 2.6 Hz, 1H), 6.73 (d, J = 43.3 Hz, 1H), 4.52 (s, 2H), 4.28 - 4.16 (m, 3H), 4.10 - 3.86 (m, 1H), 3.24 (dd, J = 39.3, 13.1 Hz, 1H), 2.15 (d, J = 15.8 Hz, 1H), 2.01 - 1.73 (m, 2H), 1.63 - 1.51 (m, 2H), 1.45 (s, 9H), 1.32 - 1.21 (m, 3H). Step 49. a: 1-tert-butyl 2-ethyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}piperidine-1,2-dicarboxylate

To a solution of 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetic acid (400 mg, 1.95 mmol, Intermediate 12) in anhydrous THF (20 mL) at 0° C. was added isobutyl chloroformate (0.24 mL, 1.85 mmol) followed by NMM (0.21 mL, 1.95 mmol). After the mixture was stirred for 15 min, 1-tert-butyl 2-ethyl(2R,5S)-5-aminoaminopiperidine-1,2-dicarboxylate (530 mg, 1.95 mmol, Intermediate 3) was added and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C., quenched with H ₂ O (0.5 mL) and concentrated in vacuo. The residue was partitioned between EtOAc (10 mL) and H ₂ O (10 mL). The organic layer was isolated, washed with saturated _aqueous NaHCO3 (10 mL) and brine (10 mL), dried over _Na2SO4 , and concentrated in vacuo to give the title compound (90% purity, 805 mg, _1.58 mmol, 81% yield) as an off-white solid; ^1H NMR (400 MHz, chloroform-d) δ 7.98 (d, J = 2.6 Hz, 1H), 7.12 (dd, J = 8.8, 2.6 Hz, 1H), 6.73 (d, J = 43.3 Hz, 1H), 4.52 (s, 2H), 4.28 - 4.16 (m, 3H), 4.10 - 3.86 (m, 1H), 3.24 (dd, J = 39.3, 13.1 Hz, 1H), 2.15 (d, J = 15.8 Hz, 1H), 2.01 - 1.73 (m, 2H), 1.63 - 1.51 (m, 2H), 1.45 (s, 9H), 1.32 - 1.21 (m, 3H).

ＴＨＦ（２．５ｍＬ）／ＭｅＯＨ（２．５ｍＬ）／Ｈ_２Ｏ（２．５ｍＬ）中の１－ｔｅｒｔ－ブチル２－エチル（２Ｒ，５Ｓ）－５－｛２－［（６－クロロ－５－フルオロピリジン－３－イル）オキシ］アセトアミド｝ピペリジン－１，２－ジカルボキシレート（９０％の純度、８０５ｍｇ、１．５８ｍｍｏｌ）およびＬｉＯＨ・Ｈ_２Ｏ（８１ｍｇ、１．８９ｍｍｏｌ）の溶液を、室温で６時間の間撹拌した。反応混合物を真空中で濃縮し、残留物をＥｔＯＡｃ（２０ｍＬ）とＨ_２Ｏ（２０ｍＬ）との間で分配した。層を分離させ、有機層を捨てた。水性層を０℃に冷却し、１ＭのＨＣｌ水溶液でｐＨ２／３に酸性化した。結果として生じた溶液をＥｔＯＡｃ（２×２５ｍＬ）で抽出し、合わせた有機抽出物をＨ_２Ｏ（３０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（９０％の純度、５７０ｍｇ、１．１９ｍｍｏｌ、７５％の収率）白色の固体として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (d, J = 6.9 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.66 (dd, J = 10.3, 2.3 Hz, 1H), 4.75 - 4.44 (m, 3H), 3.99 - 3.71 (m, 2H), 3.15 - 2.90 (m, 2H), 2.08 - 1.84 (m, 2H), 1.67 - 1.55 (m, 1H), 1.54 - 1.41 (m, 1H), 1.37 (s, 9H). Step 49. b: (2R,5S)-1-[(tert-butoxy)carbonyl]-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamide}piperidine-2-carboxylic acid

A solution of 1-tert-butyl 2-ethyl(2R,5S)-5-{ ₂ -[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}piperidine-1,2-dicarboxylate (90% purity, 805 mg, 1.58 mmol) and LiOH.H ₂ O (81 mg, 1.89 mmol) in THF (2.5 mL)/MeOH (2.5 mL)/H 2 O (2.5 mL) was stirred at room temperature for 6 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc (20 mL) and H ₂ O (20 mL). The layers were separated and the organic layer was discarded. The aqueous layer was cooled to 0° C. and acidified to pH 2/3 with 1 M aqueous HCl. The resulting solution was extracted with EtOAc (2×25 mL) and the combined organic extracts were washed with H ₂ O (30 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound (90% purity, 570 mg, 1.19 mmol, 75% yield) as a white solid; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.12 (d, J = 6.9 Hz, 1H), 8.03 (d, J = 2.6 Hz, 1H), 7.66 (dd, J = 10.3, 2.3 Hz, 1H), 4.75 - 4.44 (m, 3H), 3.99 - 3.71 (m, 2H), 3.15 - 2.90 (m, 2H), 2.08 - 1.84 (m, 2H), 1.67 - 1.55 (m, 1H), 1.54 - 1.41 (m, 1H), 1.37 (s, 9H).

無水ＴＨＦ（１１ｍＬ）中の（２Ｒ，５Ｓ）－１－［（ｔｅｒｔ－ブトキシ）カルボニル］－５－｛２－［（６－クロロ－５－フルオロピリジン－３－イル）オキシ］アセトアミド｝ピペリジン－２－カルボン酸（９０％の純度、５３０ｍｇ、１．１０ｍｍｏｌ）の溶液に０℃で、クロロギ酸イソブチル（０．１４ｍＬ、１．０５ｍｍｏｌ）、続いてＮＭＭ（０．１２ｍＬ、１．１０ｍｍｏｌ）を添加した。混合物を１５分間撹拌した後に、３，４－ジクロロベンゾヒドラジド（２２６ｍｇ、１．１０ｍｍｏｌ）を添加し、結果として生じた混合物を室温で１時間撹拌した。反応混合物を０℃に冷却し、Ｈ_２Ｏ（０．５ｍＬ）でクエンチし、真空中で濃縮した。残留物をＥｔＯＡｃ（１５ｍＬ）とＨ_２Ｏ（１５ｍＬ）との間で分配した。有機層を単離し、飽和ＮａＨＣＯ_３水溶液（１０ｍＬ）およびブライン（１０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮することで、標題化合物が（９０％の純度、６２６ｍｇ、０．９１０ｍｍｏｌ、８２％の収率）オフホワイトの固体として得られた；¹H NMR (400 MHz, chloroform-d) δ 8.68 (s, 2H), 8.00 (d, J = 2.6 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.66 - 7.59 (m, 1H), 7.56 - 7.50 (m, 1H), 7.13 (dd, J = 8.8, 2.6 Hz, 1H), 5.00 - 4.82 (m, 1H), 4.58 - 4.46 (m, 2H), 4.28 - 4.08 (m, 2H), 3.33 (d, J = 12.5 Hz, 1H), 2.25 - 2.16 (m, 1H), 2.09 - 1.84 (m, 2H), 1.83 - 1.71 (m, 1H), 1.54 - 1.44 (m, 10H). Step 49. c: tert-Butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamide}-2-[N'-(3,4-dichlorobenzoyl)hydrazinecarbonyl]piperidine-1-carboxylate

To a solution of (2R,5S)-1-[(tert-butoxy)carbonyl]-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamide}piperidine-2-carboxylic acid (90% purity, 530 mg, 1.10 mmol) in anhydrous THF (11 mL) at 0° C. was added isobutyl chloroformate (0.14 mL, 1.05 mmol) followed by NMM (0.12 mL, 1.10 mmol). After the mixture was stirred for 15 min, 3,4-dichlorobenzohydrazide (226 mg, 1.10 mmol) was added and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0° C., quenched with H ₂ O (0.5 mL) and concentrated in vacuo. The residue was partitioned between EtOAc (15 mL) and H ₂ O (15 mL). The organic layer was isolated, washed with saturated _aqueous NaHCO3 (10 mL) and brine (10 mL), dried over _Na2SO4 , and concentrated in vacuo to give the title compound (90% purity, ₆₂₆ mg, 0.910 mmol, 82% yield) as an off-white solid; ^1H NMR (400 MHz, chloroform-d) δ 8.68 (s, 2H), 8.00 (d, J = 2.6 Hz, 1H), 7.92 (d, J = 1.8 Hz, 1H), 7.66 - 7.59 (m, 1H), 7.56 - 7.50 (m, 1H), 7.13 (dd, J = 8.8, 2.6 Hz, 1H), 5.00 - 4.82 (m, 1H), 4.58 - 4.46 (m, 2H), 4.28 - 4.08 (m, 2H), 3.33 (d, J = 12.5 Hz, 1H), 2.25 - 2.16 (m, 1H), 2.09 - 1.84 (m, 2H), 1.83 - 1.71 (m, 1H), 1.54 - 1.44 (m, 10H).

無水ＡＣＮ（１０ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－｛２－［（６－クロロ－５－フルオロピリジン－３－イル）オキシ］アセトアミド｝－２－［Ｎ’－（３，４－ジクロロベンゾイル）ヒドラジンカルボニル］ピペリジン－１－カルボキシレート（６０１ｍｇ、０．９７１ｍｍｏｌ）、ＴｓＣｌ（５５５ｍｇ、２．９１ｍｍｏｌ）およびＫ_２ＣＯ_３（８０５ｍｇ、５．８３ｍｍｏｌ）の懸濁液を、８０℃で４時間の間撹拌した。反応混合物を室温に冷却し、ＥｔＯＡｃ（２０ｍＬ）とＨ_２Ｏ（２０ｍＬ）との間で分配した。層を分離させ、水性層をさらにＥｔＯＡｃ（１０ｍＬ）で抽出した。合わせた有機抽出物を飽和ＮａＨＣＯ_３水溶液（５×２０ｍＬ）およびブライン（２０ｍＬ）で洗浄し、Ｎａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。残留物をシリカゲル（ヘプタン中４０～９０％のＥｔＯＡｃ）上のクロマトグラフィーによって精製することで、標題化合物が（３１０ｍｇ、０．４９０ｍｍｏｌ、５０％の収率）オフホワイトの固体として得られた；¹H NMR (500 MHz, chloroform-d) δ 8.10 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.87 (dd, J = 8.4, 2.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 8.8, 2.6 Hz, 1H), 6.77 (s, 1H), 5.93 - 5.44 (m, 1H), 4.62 - 4.48 (m, 2H), 4.29 - 4.19 (m, 1H), 4.17 - 4.02 (m, 1H), 3.43 - 2.98 (m, 1H), 2.38 - 2.23 (m, 1H), 2.18 - 1.91 (m, 3H), 1.50 (s, 9H). [Example 99]
(Step 49.d): tert-Butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate

A suspension of tert-butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[N'-(3,4-dichlorobenzoyl)hydrazinecarbonyl]piperidine-1-carboxylate (601 mg, 0.971 mmol), TsCl (555 mg, 2.91 mmol) and _K2CO3 (805 mg, 5.83 mmol) in anhydrous _ACN (10 mL) was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (20 mL) and _H2O (20 mL). The layers were separated and the aqueous layer was further extracted with _EtOAc (10 mL). The combined organic extracts were washed with saturated aqueous _NaHCO3 (5 x 20 mL) and brine (20 mL), dried over _Na2SO4 and concentrated in vacuo. The residue was purified by chromatography on silica gel (40-90% EtOAc in heptane) to give the title compound (310 mg, 0.490 mmol, 50% yield) as an off-white solid; ¹ H NMR (500 MHz, chloroform-d) δ 8.10 (d, J = 2.0 Hz, 1H), 8.01 (d, J = 2.6 Hz, 1H), 7.87 (dd, J = 8.4, 2.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 8.8, 2.6 Hz, 1H), 6.77 (s, 1H), 5.93 - 5.44 (m, 1H), 4.62 - 4.48 (m, 2H), 4.29 - 4.19 (m, 1H), 4.17 - 4.02 (m, 1H), 3.43 - 2.98 (m, 1H), 2.38 - 2.23 (m, 1H), 2.18 - 1.91 (m, 3H), 1.50 (s, 9H).

ＤＣＭ（３ｍＬ）中のｔｅｒｔ－ブチル（２Ｒ，５Ｓ）－５－｛２－［（６－クロロ－５－フルオロピリジン－３－イル）オキシ］アセトアミド｝－２－［５－（３，４－ジクロロフェニル）－１，３，４－オキサジアゾール－２－イル］ピペリジン－１－カルボキシレート（１５０ｍｇ、０．２５０ｍｍｏｌ、実施例９９）の溶液に、ＺｎＢｒ_２（２２５ｍｇ、０．９９９ｍｍｏｌ）を添加し、結果として生じた混合物を室温で１８時間の間撹拌した。反応混合物を飽和ＮａＨＣＯ_３水溶液（２ｍＬ）とＤＣＭ／ＩＰＡ（４：１、２ｍＬ）との間で分配し、相分離器を使用して層を分離させた。有機層を真空中で濃縮し、分取ＨＰＬＣ（方法４）によって精製することで、標題化合物が（２８ｍｇ、０．０５５４ｍｍｏｌ、２２％の収率）オフホワイトの粉末として得られた；¹H NMR (500 MHz, chloroform-d) δ 8.17 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 2.6 Hz, 1H), 7.93 (dd, J = 8.4, 2.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.18 (dd, J = 8.8, 2.6 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 4.57 (s, 2H), 4.27 - 4.21 (m, 1H), 4.20 - 4.09 (m, 1H), 3.41 (dd, J = 12.1, 3.3 Hz, 1H), 2.73 (dd, J = 12.1, 7.7 Hz, 1H), 2.29 - 2.20 (m, 1H), 2.20 - 2.04 (m, 3H), 1.78 - 1.67 (m, 1H); M/Z: 500, 502, 504, 506 [M+H]⁺, ESI⁺, RT = 2.18 (S4). [Example 100]
(Step 49.e): 2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-[(3S,6R)-6-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide

To a solution of tert-butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate (150 mg, 0.250 mmol, Example 99) in DCM (3 mL) was added ZnBr ₂ (225 mg, 0.999 mmol) and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between saturated aqueous NaHCO ₃ (2 mL) and DCM/IPA (4:1, 2 mL) and the layers were separated using a phase separator. The organic layer was concentrated in vacuo and purified by preparative HPLC (Method 4) to give the title compound (28 mg, 0.0554 mmol, 22% yield) as an off-white powder; ¹ H NMR (500 MHz, chloroform-d) δ 8.17 (d, J = 2.0 Hz, 1H), 8.05 (d, J = 2.6 Hz, 1H), 7.93 (dd, J = 8.4, 2.0 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.18 (dd, J = 8.8, 2.6 Hz, 1H), 6.73 (d, J = 7.8 Hz, 1H), 4.57 (s, 2H), 4.27 - 4.21 (m, 1H), 4.20 - 4.09 (m, 1H), 3.41 (dd, J = 12.1, 3.3 Hz, 1H), 2.73 (dd, J = 12.1, 7.7 Hz, 1H), 2.29 - 2.20 (m, 1H), 2.20 - 2.04 (m, 3H), 1.78 - 1.67 (m, 1H); M/Z: 500, 502, 504, 506 [M+H] ⁺ , ESI ⁺ , RT = 2.18 (S4).

Scheme for Route 50

ＤＭＦ（２ｍＬ）中の２－（４－クロロ－３－フルオロフェノキシ）－Ｎ－［（３Ｓ，６Ｒ）－６－｛５－［２－（トリフルオロメトキシ）エトキシ］－１，３，４－オキサジアゾール－２－イル｝ピペリジン－３－イル］アセトアミド（１００ｍｇ、０．１９７ｍｍｏｌ、実施例７７）およびＫ_２ＣＯ_３（５７ｍｇ、０．４１３ｍｍｏｌ）の溶液に、ＭｅＩ（１３４μＬ、２．１６ｍｍｏｌ）を添加し、混合物を室温で５日間撹拌した。反応混合物を３３％のＮＨ_４ＯＨ水溶液（１ｍＬ）でクエンチし、３０分間撹拌した。溶液をＨ_２Ｏ（３０ｍＬ）で希釈し、ＥｔＯＡｃ（２×３０ｍＬ）で抽出し、合わせた有機抽出物をＮａ_２ＳＯ_４上で乾燥させ、真空中で濃縮した。分取ＨＰＬＣ（方法５）による精製で、標題化合物が（３６ｍｇ、０．０７２５ｍｍｏｌ、３７％の収率）白色の粉末として得られた；¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.89 - 6.81 (m, 1H), 4.72 - 4.63 (m, 2H), 4.53 (s, 2H), 4.49 - 4.42 (m, 2H), 3.91 - 3.80 (m, 1H), 3.29 - 3.20 (m, 1H), 2.96 - 2.88 (m, 1H), 2.12 - 1.95 (m, 4H), 1.92 - 1.80 (m, 2H), 1.78 - 1.67 (m, 1H), 1.49 - 1.35 (m, 1H); M/Z: 497, 499 [M+H]⁺, ESI⁺, RT = 2.75 (S4). [Example 101]
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-1-methyl-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide

To a solution of 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide (100 mg, 0.197 mmol, Example 77) and K ₂ CO ₃ (57 mg, 0.413 mmol) in DMF (2 mL) was added MeI (134 μL, 2.16 mmol) and the mixture was stirred at room temperature for 5 days. The reaction mixture was quenched with 33% aqueous NH ₄ OH (1 mL) and stirred for 30 min. The solution was diluted with H ₂ O (30 mL) and extracted with EtOAc (2×30 mL) and the combined organic extracts were dried over Na ₂ SO ₄ and concentrated in vacuo. Purification by preparative HPLC (Method 5) gave the title compound (36 mg, 0.0725 mmol, 37% yield) as a white powder; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.05 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 8.9 Hz, 1H), 7.07 (dd, J = 11.4, 2.8 Hz, 1H), 6.89 - 6.81 (m, 1H), 4.72 - 4.63 (m, 2H), 4.53 (s, 2H), 4.49 - 4.42 (m, 2H), 3.91 - 3.80 (m, 1H), 3.29 - 3.20 (m, 1H), 2.96 - 2.88 (m, 1H), 2.12 - 1.95 (m, 4H), 1.92 - 1.80 (m, 2H), 1.78 - 1.67 (m, 1H), 1.49 - 1.35 (m, 1H); M/Z: 497, 499 [M+H] ⁺ , ESI ⁺ , RT = 2.75 (S4).

Scheme for Route 51

[Examples 102 and 103]
Chiral separation of 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(2,2-difluorocyclopropoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide (Example 87) 2-(4-Chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(2,2-difluorocyclopropoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide (48 mg, 0.0978 mmol, Example 87) was subjected to chiral purification using Method C4 to give 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{2-[(1R)-2,2-difluorocyclopropoxy]ethoxy}-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide. [2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{2-[(1S)-2,2-difluorocyclopropoxy]ethoxy}-1,3,4-oxadiazol-2-yl)piperidin-3-yl]acetamide (98% chiral purity, 13.3 mg, 0.0268 mmol, 27% yield) and 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{2-[(1S)-2,2-difluorocyclopropoxy]ethoxy}-1,3,4-oxadiazol-2-yl)piperidin-3-yl]acetamide (100% chiral purity, 12.4 mg, 0.025 mmol), 26% yield) were obtained as white powders. The stereochemistry of each compound was arbitrarily assigned.

Following general route 51, the example compounds in Table 22 were chiral purified using the corresponding intermediates and methods as exemplified by Examples 102 and 103.

II. Assay HEK-ATF4 High Content Imaging Assay Example compounds were tested in the HEK-ATF4 high content imaging assay to determine their pharmacological potency for preventing tunicamycin-induced ISR. Wild type HEK293 cells were plated in growth medium (DMEM/F12, 10% FBS, 2 mM L-glutamine, 100 U/mL penicillin-100 μg/mL streptomycin) at a density of 12,000 cells per well in 384-well imaging assay plates and incubated at 37° C., 5% CO _2. After 24 hours, the medium was changed to 50 μL of assay medium (DMEM/F12, 0.3% FBS, 2 mM L-glutamine, 100 U/mL penicillin-100 μg/mL streptomycin) per well. Example compounds were serially diluted in DMSO and spotted into the intermediate plate and prediluted with assay medium containing 3.3 μM tunicamycin to give an 11-fold excess of final assay concentrations. In addition to the example compound test areas, the plate also contained multiple control wells for assay normalization purposes, wells containing tunicamycin but no example compound (high control), as well as wells containing neither example compound nor tunicamycin (low control). The assay was initiated by transferring 5 μL from the intermediate plate into the assay plate, followed by incubation at 37° C., 5% CO ₂ for 6 hours. Subsequently, cells were fixed (4% PFA in PBS, 20 min at room temperature) and subjected to indirect ATF4 immunofluorescence staining (primary antibody rabbit anti-ATF4, clone D4B8, Cell Signaling Technologies; secondary antibody Alexa Fluor 488 goat anti-rabbit IgG (H+L), Thermofisher Scientific). Hoechst dye (Thermofisher Scientific) was used to stain nuclei and plates were imaged on an Opera Phoenix High Content imaging platform equipped with 405 nm and 488 nm excitation. Finally, images were analyzed using a script-based algorithm. The primary readout HEK-ATF4 monitored the ATF4 signal ratio between the nucleus and cytoplasm. Tunicamycin induced an increase in the global ATF4 ratio signal, which was prevented by ISR-modulating example compounds. In addition, the HEK-CellCount readout was derived from counting the number of stained nuclei corresponding to healthy cells. This readout served as an internal toxicity control. Example compounds herein did not produce a significant reduction in CellCount.

The HEK ATF4 activities of the tested example compounds are provided in Table 23 as follows:
+++= _IC50 1-500 nM; ++= _IC50 >500-2000 nM; +=IC50 >2000-15000 nM.

Protocol - Thermodynamic (Equilibrium) Solubility in Selection Buffer Example compounds were tested for thermodynamic (equilibrium) solubility in the selection buffer assay. Test compounds were weighed in powder form into 4 mL glass vials and the calculated volume of selection medium was added to reach the target concentration for solubility testing (1 mg/mL). The solution was then stirred overnight at room temperature protected from light. The solution was filtered through a 0.45 μm PTFE membrane at ambient temperature. An aliquot of the resulting filtrate was quantified using the UPLC-UV method described below against a reference solution of 0.8 mg/mL of test compound in DMSO. Culture medium composition: phosphate buffer 50 mM (pH = 2.0), 690 _{mg NaH2PO4.H2O} in 200 mL ultrapure water adjusted to pH ₂ with phosphoric acid 85%; acetate buffer 50 mM (pH = 5.5), 820 mg anhydrous sodium acetate in 200 mL ultrapure water adjusted to pH 5.5 with acetic acid 99.8%; phosphate buffer 50 mM (pH = 7.4), 40.5 mL of a 0.1 M solution of _Na2HPO4 + 9.5 mL _of a 0.1 M solution _{of NaH2PO4} . Analytical conditions: UPLC-UV-MS analysis was performed using a Waters Acquity UPLCH Class-PDA-QDa system using a reversed-phase Acquity BEH C18 column (2.1 mm x 50 mm, 1.7 μm; temperature: 40° C.) and a gradient of 10-95% B (A=0.1% formic acid in H ₂ O; B=0.05% formic acid in ACN) over 1.8 min, followed by 100% B in 0.8 min, with an injection volume of 0.4 μL at a flow rate of 0.65 mL/min. UV chromatograms were recorded at 220 nm, 254 nm and 290 nm using a photodiode array detector. Mass spectra were recorded using a QDa detector at a sampling rate of 10 scans per second in the 150 to 900 M/Z range. Data was integrated using Empower® 3 software. Data analysis: The equilibrium solubility of the test compound in the selective medium was calculated via the ratio of the surface area of the UV chromatographic peak of the compound in the filtrate to the surface area of the UV chromatographic peak of the compound in the reference solution.

Protocol - Measuring Effects on hERG Channels by Tail Current Recordings Using In Vitro Rapid ICE The potency of example compounds in inhibiting human ERG potassium channel (hERG) tail currents was determined using the Rapid ICE (rapid ion channel electrophysiology) assay in a recombinant HEK293 cell line stably transfected with hERG cDNA under an inducible promoter. Rapid ICE is an automated patch-clamp assay utilizing the QPatch HTX system (Sophion Bioscience A/S). Briefly, inducible HEKhERG cells were cultured in minimal essential medium supplemented with 10% FBS, 1% non-essential amino acids, 1% sodium pyruvate, 2 mM l-glutamine, 15 μg/mL blasticidin, and 100 μg/mL hygromycin. Induction of hERG channel expression was obtained by adding 10 μg/mL tetracycline for 24, 48 or 72 hours prior to recording.

On the day of the experiment, cells were detached with TrypLE and prepared to be loaded onto the instrument. Cells were resuspended in 7 mL serum-free medium containing 25 mM Hepes and soybean trypsin inhibitor and immediately placed into the cell storage tank of the machine. The composition of the extracellular buffer was (in mM): NaCl 137, KCl 4, _CaCl2 1.8, _MgCl2 1.0, d-glucose 10, N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES) 10, 1 M NaOH pH 7.4. The composition of the intracellular solution was (in mM): KCl 130, _MgCl2 1.0, ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) 5, MgATP 5, HEPES 10, 1 M KOH pH 7.2. The voltage protocol included the following steps: -80 mV to -50 mV for 200 ms, step to +20 mV for 4.8 s, step to -50 mV for 5 s, then step to a holding potential of -80 mV. Compounds were dissolved in DMSO and diluted in extracellular buffer to achieve final test concentrations (0.3, 3 and 30 μM) in 0.3% DMSO. The voltage protocol was run and recorded continuously during the experiment. Vehicle corresponding to 0.3% DMSO in extracellular buffer was then applied for 3 min, followed by the test substance in triplicate. The standard combination exposure time was 5 min. The effect of the test substance was calculated for each cell by calculating the residual current (% control) compared to vehicle pretreatment using the average of the tail current amplitude values recorded from four sequential voltage pulses. Data were reported as % inhibition for each concentration tested, and _IC50 values were estimated using QPatch software. At least two cells were tested, and if results were discrepant, more cells.

Protocol - LogD7.4 Assay Phosphate buffer (1M) was diluted to 20 mM with deionized water and adjusted to pH 7.4 (±0.05) with phosphoric acid or sodium hydroxide. A 1:1 mixture of phosphate buffer (20 mM) and 1-octanol was saturated by rotating overnight, after which time the two phases were allowed to separate. Using an automated liquid handler, the following procedure was performed: 20 mM DMSO stocks of assay and control compounds were reformatted to provide cassettes of 4 compounds per well giving a final concentration of 5 mM per compound. In duplicate, 5 μL of cassette compound was added to 495 μL of 1-octanol (saturated with buffer) followed by 495 μL of buffer (saturated with 1-octanol) in a 96-well plate to give a final incubation concentration of 25 μM (max concentration of 50 μM in either layer if all compounds were distributed into a single matrix). The layers were mixed by aspirating and dispensing the buffer and octanol layers into each other three times. The plate was sealed and shaken for 120 minutes, then centrifuged at 4600 rpm for 15 minutes at 25° C. The 1-octanol and buffer layers were sampled separately (to ensure no cross contamination) and each sample was diluted with 60:40 ACN:0.1 M ammonium acetate pH 7.4 (containing an external standard; sulfisoxazole, assay concentration 120 nM) to give final theoretical maximum concentrations of 0.025 μM, 0.5 μM 1-octanol layer and 0.5 μM buffer layer concentrations. A second buffer sample was prepared by diluting the assay buffer layer with acetonitrile (containing an external standard; sulfisoxazole, assay concentration 120 nM) to give a theoretical maximum concentration of 20 μM. Analytical samples were analyzed by LC-MS/MS and LogD was calculated as shown below:

Where PA = peak area and ES = external standard.

Biological Example: Lipophilicity and Solubility In recent years, there have been numerous reports in the medicinal chemistry literature relating the clinical success of drug candidates to their physicochemical properties. The degree of lipophilicity, in particular, has been highlighted as an important factor in defining the overall properties and likely fate of a drug candidate (29), and typically it is beneficial if the logD is in the range of 1 to 3. With reference to Table 24, selected compounds of the present invention have logD values that fall within this range, and in this respect represent an improvement over previously reported and similar analogs.

Similarly, poor solubility of a drug candidate is associated with an increased risk of drug development failure (30). Moreover, with reference to Table 24, select compounds of the present invention exhibit higher aqueous solubility compared to structurally similar compounds in the state of the art. Additional solubility data relating to further example compounds is presented in Table 25 below.

Biological Example: hERG Selectivity Drug-induced QT interval prolongation and the occurrence of torsade de pointes (TdP) are well-recognized clinical risks. While these effects are often multifactorial, there is a clear consensus in recognizing the role that drug interactions with cardiac hERG K ⁺ channels play in the manifestation of these clinical side effects. In general, it is widely accepted that it is desirable to minimize the interaction of drug molecules with the hERG K ⁺ channel (31). To this end, we sought to balance the improvement of the physicochemical properties described above (i.e. logD and solubility - Tables 24 & 25) with selective modulation of ATF4 relative to the hERG K ⁺ channel.

With reference to Tables 23, 25 and 26, selected compounds of the present invention exhibit an advantageous balance of properties, particularly with respect to HEK ATF4 activity and/or solubility and/or selective hERG inhibition.

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Claims (49)

Formula (I)

or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof,
^X1 is N(R ^a1 );
X ^1a is CH (R ^a3 ) ;
R ^a1 is H, C(O)OC _1-4 alkyl or C _1-4 alkyl, where C(O)OC _1-4 alkyl and C _1-4 alkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, OH and O—C _1-3 alkyl, where the substituents are the same or different;
R ^a2 , R ^a3 are independently selected from the group consisting of H, OH, OC _1-4 alkyl, halogen, C _1-4 alkyl, and A ^2a ;
R ^a4 , R ^a5 , R ^a6 , and R ^a7 are independently selected from the group consisting of H, halogen, C _1-4 alkyl, and A ^2a ;
With the proviso that exactly one of R ^a2 , R ^a3 , R ^a4 , R ^a5 , R ^a6 , and R ^a7 is A ^2a ;
or R ^a1 and one of R ^a2 and R ^a3 form a methylene or ethylene group;
or R ^a1 and R ^a6 form an ethylene group;
or R ^a2 and R ^a5 form a covalent single bond;
or R ^a5 and R ^a7 are connected to form an oxo group;
A ¹ is a C ₅ cycloalkylene, a C ₅ cycloalkenylene, or a nitrogen ring atom-containing 5-membered heterocyclene, where A ¹ is optionally substituted with one or more R ⁴ , which may be the same or different;
each ^R4 is independently an at least partially saturated ring oxo (=O), an at least partially saturated ring thioxo (=S), halogen, CN, ^OR5 , or _C1-6 alkyl, wherein _C1-6 alkyl is optionally substituted with one or more halogens which may be the same or different;
R ⁵ is H or C _1-6 alkyl, where C _1-6 alkyl is optionally substituted with one or more halogens which may be the same or different;
^A2 is ^R6a or ^A2a ;
R ^6a is O 2 R ^6a1 , R ^6a1 is A ^2a or C _1-6 alkyl optionally substituted with one or more halogens and/or one A ^2a and/or one OR ^6a3 ; or R ^6a is C _1-6 alkyl optionally substituted with one or more halogens and/or one A ^2a and/or one OR ^6a3 ;
R ^6a3 is H or C _1-4 alkyl, where C _1-4 alkyl is optionally substituted with one or more halogens which may be the same or different;
A ^2a is phenyl, C _3-7 cycloalkyl, C _{4-12 bicycloalkyl, or 3- to} 7-membered heterocyclyl, where A ^2a is optionally substituted with one or more R ⁶ which are the same or different;
each R ⁶ is independently R ^6b , OH, OR ^6b , halogen, or CN, where R ^6b is cyclopropyl, C _1-6 alkyl, C _2-6 alkenyl, or C _2-6 alkynyl, where R ^6b is optionally substituted with one or more halogens which are the same or different; or two R ⁶ are connected to form, together with the atom to which they are attached, a ring A ^2b ;
A ^2b is phenyl, C _{3-7 cycloalkyl, or 3- to 7-} membered heterocyclyl, where A ^2b is optionally substituted with one or more R ⁷ which are the same or different;
each R ⁷ is independently a C _1-6 alkyl, a C _2-6 alkenyl, or a C _2-6 alkynyl, wherein the C _1-6 alkyl, the C _2-6 alkenyl, and the C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different;
R ¹ is H or C _1-4 alkyl , where C _1-4 alkyl is optionally substituted with one or more halogens which may be the same or different;
^R2 is H, F, or _C1-4 alkyl, where _C1-4 alkyl is optionally substituted with one or more halogens which may be the same or different;
R ³ is A ³ , C _1-6 alkyl, C _2-6 alkenyl or C _2-6 alkynyl, where C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with one or more R ⁸ , which are the same or different; or R ² and R ³ are connected to form, together with the oxygen atom and the carbon atom to which they are attached, a ring A ^3a , where A ^3a is a 7- to 12-membered heterobicyclyl, where the 7- to 12-membered heterobicyclyl is optionally substituted with one or more R ¹⁰ , which are the same or different;
R ^2a is H or F ;
Each R ⁸ is independently halogen, CN, C(O)OR ⁹ , OR ⁹ , C(O)R ⁹ , C(O)N(R ⁹ R ^9a ), S(O) ₂ N(R ⁹ R ^9a ), S(O)N(R ⁹ R ^9a ), S(O) ₂ R ⁹ , S(O)R ⁹ , N(R ⁹ )S(O) ₂ N(R ^9a R ^9b ), SR ⁹ , N(R ⁹ R ^9a ), NO ₂ , OC(O)R ⁹ , N(R ⁹ )C(O)R ^9a , N(R ⁹ )SO ₂ R ^9a , N(R ⁹ )S(O)R ^9a , N(R ⁹ )C(O)N(R ^9a R ^9b ), N(R ⁹ )C(O)OR ^9a , OC(O)N(R ⁹ R ^9a ), or A ³ ;
R ⁹ , R ^9a , R ^9b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl and C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different, or one OH, or one OC _1-4 alkyl, or one A ³ ;
each ^A3 is independently phenyl, naphthyl, C3-7cycloalkyl, 3- _{to 7-} membered heterocyclyl, or 7- to 12-membered heterobicyclyl, where ^A3 is optionally substituted with one or more ^R10 , which may be the same or different;
Each R ¹⁰ is independently halogen, CN, C(O)OR ¹¹ , OR ¹¹ , C(O)R ¹¹ , C(O)N(R ¹¹ R ^11a ), S(O) ₂ N(R ¹¹ R ^11a ), S(O)N(R ¹¹ R ^11a ), S(O) ₂ R ¹¹ , S(O)R ¹¹ , N(R ¹¹ )S(O) ₂ N(R ^11a R ^11b ), SR ¹¹ , N(R ¹¹ R ^11a ), NO ₂ , OC(O)R ¹¹ , N(R ¹¹ )C(O)R ^11a , N(R ¹¹ )S(O) ₂ R ^11a , N(R ¹¹ )S(O)R ^lla , N(R ¹¹ )C(O)OR ^11a , N(R ¹¹ )C(O)N(R ^11a R ^11b ), OC(O)N(R ¹¹ R ^11a ), oxo (═O) where the ring is at least partially saturated, C _1-6 alkyl, C _{2-6 alkenyl, or C 2-6 alkynyl} , where C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more R ¹² which may be the same or different;
R ¹¹ , R ^11a , R ^11b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different;
each ^R12 is independently halogen, CN, C(O) ^OR13 , ^OR13 , C(O) ^R13 , C(O)N( ^R13R13a ), S(O) _2N ( ^R13R13a ), S(O)N( ^R13R13a ), ^S (O) _2R13 ^, S(O) ^R13 , N( ^R13 )S( ^O ) _2N ( ^{R13aR13b ), SR13 , N} ( ^R13R13a ), _NO2 , OC(O) ^{R13 ,} N( ^R13 )C(O) ^R13a , N( ^R13 ) _SO2R13a , N( ^R13 )S ⁽ O) ^R13a , N( ^R13 )C(O)N ^{(R13aR13b )} , ^N ( ^R13 )C(O) ^OR13a , or OC(O)N( ^R13R13a );
R ¹³ , R ^13a , R ^13b are independently selected from the group consisting of H, C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl, wherein C _1-6 alkyl, C _2-6 alkenyl, and C _2-6 alkynyl are optionally substituted with one or more halogens, which may be the same or different. R ¹ is H, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. R ^2a is H, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. 4. The compound of any one of claims _{1 to 3} , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein ^X1 is NH or N-Ci _-4 alkyl, where Ci _-4 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, and O-Ci-3 alkyl , wherein the substituents are the same or different . X ¹ is NH, N(CH ₃ ), N(CH ₂ CH ₃ ), or N(CH ₂ CH ₂ OCH ₃ 5. The compound of claim 4, wherein: X ¹ is NH or N(CH ₃ 6. The compound of claim 5, wherein: X ¹ 7. The compound of claim 6, wherein is NH, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. R ^a2 , R ^a3 are independently selected from the group consisting of H, OH, OC _1-4 alkyl, halogen, C _1-4 alkyl, and A ^2a ;
R ^a4 , R ^a5 , R ^a6 , and R ^a7 are independently selected from the group consisting of H, halogen, C _1-4 alkyl, and A ^2a , with the proviso that only one of R ^a2 , R ^a3 , R ^a4 , R ^a5 , R ^a6 , and R ^a7 is A ^2a ;
or R ^a5 and R ^a7 are connected to form an oxo group;
8. A compound according to any one of claims 1 to 7 , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof. R ^a2 , R ^a3 , R ^a4 , R ^a5 , R ^a6 , R ^a7 is H, or R ^a2 , R ^a3 , R ^a4 , R ^a6 is H, and R ^a5 , R ^a7 is connected to form an oxo group, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. 10. The compound of any one of claims 1 to 9 , wherein R ^a2 , R ^a3 , R ^a4 , R ^a5 , R ^a6 , and R ^a7 are H, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. A compound according to any one of claims 1 to 10 , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein ^A1 is a nitrogen ring atom-containing 5-membered heterocyclene, and ^A1 is optionally substituted with one or more ^R4s , which may be the same or different. A ¹ is a nitrogen ring atom-containing 5-membered heterocycle selected from the group of divalent heterocycles consisting of oxadiazole, imidazole, imidazolidine, pyrazole and triazole, and A ¹ is optionally substituted with one or more R ⁴ , which may be the same or different. A compound according to any one of claims 1 to 11 , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof. A ¹ is oxadiazole, A ¹ represents one or more R ⁴ 13. The compound of claim 12, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, optionally substituted with: A compound according to any one of claims 1 to 13 , wherein A ¹ is unsubstituted or substituted with one or two R ^{4 ,} which are the same or different, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof. A ¹ is unsubstituted, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. 16. The compound of any one of claims 1 to 15 , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein ^R4 is oxo, the ring being at least partially saturated. ^A1 is,

17. The compound of any one of claims 1 to 16 , wherein: 18. The compound of any one of claims 1 to 17 , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein ^A2 is ^R6a . 19. The compound of claim 18 , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein R ^6a is _C1-6 alkyl optionally substituted with one or more halogens and/or one OR ^6a3 , or R ^6a is OR ^6a1 . R ^6a1 is one or more F and/or one OR ^6a3 C optionally substituted with _1-6 20. The compound of claim 19, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein: R ^6a1 is CH ₂ CH ₂ CF ₃ or CH ₂ CH ₂ O.C.F. ₃ 21. The compound of claim 20, wherein: R ^6a1 is CH ₂ CH ₂ O.C.F. ₃ 22. The compound of claim 21 , wherein: 18. The compound of any one of claims 1 to 17 , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein ^A2 is ^A2a . 24. The compound of claim 23, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein ^A2a is phenyl, cyclobutyl, azetidinyl, pyrrolidinyl, or a 5- to 6- membered aromatic heterocyclyl , and ^A2a is optionally substituted with one or more ^R6 , which may be the same or different. A ^2a is pyridyl, pyrazinyl, pyridazinyl, pyrazolyl or 1,2,4-oxadiazolyl; A ^2a represents one or more R ⁶ 25. The compound of claim 24, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, optionally substituted with: 26. The compound of any one of claims 1 to 17, 23 to 25 , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein ^A2a is substituted with one or two ^R6 , which are the same or different. A compound according to any one of claims 1 to 17, 23 to ₂₆ , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein each ^R6 is independently F , _Cl , _CF3 , _OCH3 , _OCHF2 , _OCF3 , _CH3 , _CH2CH3 , _CH2CF3 , O-cyclopropyl or cyclopropyl. 28. The compound of any one of claims 1 to 27 , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein ^R2 is _CH3 , F, or H. R ² is H, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. 30. The compound of any one of claims 1 to 29 , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein ^R3 is ^A3 . 31. The compound of any one of claims 1 to 30 , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein ^A3 is phenyl, pyridyl, pyrazinyl, pyrimidazyl, cyclopropyl, cyclobutyl or cyclohexyl , and ^A3 is optionally substituted with one or more ^R10 , which are the same or different. A ³ is phenyl, A ³ represents one or more R ¹⁰ 32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, optionally substituted with: 33. The compound of any one of claims 1 to 32, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein ^A3 is substituted with one, two or three R10 ^, which are the same or different. A ³ is one or two R ¹⁰ 34. The compound of claim 33, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein 35. The compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, wherein ^R2 and ^R3 , together with the oxygen and the carbon atom to which they are attached, are connected to form a dihydrobenzopyran ring, wherein the ring is optionally substituted with one or more R10, which may be the ^same or different. The ring may be formed by one or two identical or different R ¹⁰ 36. The compound of claim 35, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, optionally substituted with 37. The compound of any one of claims 1 to 36 , wherein ^R10 is independently F, Cl, Br, CN, _CHF2 , _CF3 , _OCH3 , _OCF3 , CH=O, _CH2OH or _CH3 , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof. 38. The compound of any one of claims 1 _{to 37} , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof, wherein R ^a1 is H or C _1-4 alkyl, wherein C _1-4 alkyl is optionally substituted with one or more substituents selected from the group consisting of halogen, OH, and O-C 1-3 alkyl, wherein the substituents are the same or different . R ^a1 is H, CH ₃ or CH ₂ CH ₃ 40. The compound of claim 38, wherein: tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
tert-butyl (2R,5S)-5-[2-(4-chlorophenoxy)propanamido]-2-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate,
2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]propanamide,
N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]-2-[(1s,3s)-3-(trifluoromethoxy)cyclobutoxy]acetamide,
tert-butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate,
2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
tert-butyl (2R,5S)-5-[2-(3,4-dichlorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate,
2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-[3-chloro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-[4-chloro-3-(difluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(4-chloro-3-methylphenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(3,4-dimethylphenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]-2-{[6-(trifluoromethyl)pyridin-3-yl]oxy}acetamide,
2-[3-methoxy-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
tert-butyl (2R,5S)-5-[2-(4-chloro-2-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate,
2-(4-chloro-2-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(3-chloro-4-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-[4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-2,3-difluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3,5-difluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-[3-fluoro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-2,2-difluoro-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-[3-chloro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(3,4,5-trichlorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-bromophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-[3-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-cyanophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide ,
tert -butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(6-methylpyridin-3-yl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3R,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
rac-2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-oxopiperidin-3-yl]acetamide,
rac-2-(4-chloro-3-fluorophenoxy)-N-[(3R,6R)-2-oxo-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
tert-butyl (2S,5R)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate,
2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(3,3,3-trifluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-{5-[3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-methylpiperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-methylpiperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethylpiperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-ethylpiperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-1-(2-methoxyethyl)piperidin-3-yl]acetamide,
tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
N-[(3S,6R)-6-[5-(5-chloro-1-methyl-1H-pyrazol-3-yl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[6-(trifluoromethyl)pyridin-3-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(5-chloropyridin-2-yl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chloro-3-fluorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethoxy)propyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[1-(2,2,2-trifluoroethyl)azetidin-3-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-cyclopropoxycyclobutyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(difluoromethoxy)cyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(trifluoromethoxy)methyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3,3-trifluoro-2-methylpropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(4,4,4-trifluorobutan-2-yl)oxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3-difluorobutoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(2,2-difluorocyclopropyl)methoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
N-[(3S,6R)-6-(5-butoxy-1,3,4-oxadiazol-2-yl)piperidin-3-yl]-2-(4-chloro-3-fluorophenoxy)acetamide 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(3,3-difluorocyclopentyl)oxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2-cyclopropylethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-methylbutoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(2,2-difluorocyclobutyl)methoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3,3-difluorocyclobutoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2,2,3,3,3-pentafluoropropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4,4,4-trifluorobutoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(difluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(pentyloxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-methoxypropoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide ,
2- (4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(2-ethoxyethoxy)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide ,
2- (4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(
4,4-difluoropentyl)oxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(3,4-dichlorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide ,
2- (4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-(5-{[2-(trifluoromethyl)cyclopropyl]methoxy}-1,3,4-oxadiazol-2-yl)piperidin-3-yl]acetamide,
tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[3-(trifluoromethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidine-1-carboxylate,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(2,2,2-trifluoroethyl)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-methyl-3-(trifluoromethoxy)azetidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide ,
2- (4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(3-cyclopropoxyazetidin-1-yl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[3-(trifluoromethoxy)pyrrolidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
tert-butyl (2R,5S)-5-[2-(4-chloro-3-fluorophenoxy)acetamido]-2-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-3-yl}piperidine-1-carboxylate,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-(trifluoromethoxy)cyclobutyl]-1,2,4-oxadiazol-3-yl}piperidin-3-yl]acetamide,
tert-butyl (2R,5S)-5-{2-[(6-chloro-5-fluoropyridin-3-yl)oxy]acetamido}-2-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]piperidine-1-carboxylate,
2-[(6-chloro-5-fluoropyridin-3-yl)oxy]-N-[(3S,6R)-6-[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-1-methyl-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide ,
2- (4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1r,3r)-3-cyclopropoxycyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(1s,3s)-3-cyclopropoxycyclobutyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
(2R)-2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]propanamide,
(2S)-2-(4-chlorophenoxy)-N-[(3S,6R)-6-{5-[4-(trifluoromethyl)phenyl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]propanamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-oxopiperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-2-oxopiperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(3S)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[(3R)-3-(trifluoromethoxy)pyrrolidin-1-yl]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide,
N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]-2-[4-(trifluoromethyl)phenoxy]acetamide,
40. The compound according to any one of claims 1 to 39, which is 2-[3-chloro-4-(difluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol- 2 -yl}piperidin-3-yl]acetamide, or 2-[3-fluoro-4-(trifluoromethyl)phenoxy]-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer, or stereoisomer thereof. A compound which is 2-(4-chloro-3-fluorophenoxy)-N-[(3S,6R)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide or a pharma- ceutically acceptable salt thereof. A compound which is 2-(4-chloro-3-fluorophenoxy)-N-[(3R,6S)-6-{5-[2-(trifluoromethoxy)ethoxy]-1,3,4-oxadiazol-2-yl}piperidin-3-yl]acetamide or a pharma- ceutically acceptable salt thereof. A compound of the formula: or a pharma- ceutically acceptable salt thereof.

A compound of the formula: or a pharma- ceutically acceptable salt thereof.

Formula (Ia)

45. The compound of any one of claims 1 to 44 , wherein: 46. A pharmaceutical composition comprising at least one compound as defined in any one of claims 1 to 45 , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, together with a pharma- ceutically acceptable carrier, optionally in combination with one or more other biologically active compounds or pharmaceutical compositions. Use of a compound as defined in any one of claims 1 to 45 , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition as defined in claim 46 , for the manufacture of a medicament for the treatment or prevention of one or more diseases or disorders associated with the integrated stress response. 47. Use of a compound as defined in any one of claims 1 to 45, or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition as defined in claim 46, for the manufacture of a medicament for the treatment or prevention of one or more diseases or disorders selected from the group consisting of leukodystrophies, intellectual disability syndromes, neurodegenerative diseases and disorders, neoplastic diseases, infectious diseases, inflammatory diseases, musculoskeletal diseases, metabolic diseases, ocular diseases, as well as one or more diseases selected from the group consisting of organ fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lungs, chronic and acute diseases of the kidneys, myocardial infarction, cardiovascular diseases, arrhythmias, atherosclerosis, spinal cord injury, ischemic stroke, and neuropathic pain. 47. Use of a compound as defined in any one of claims 1 to 45 , or a pharma- ceutically acceptable salt, solvate, hydrate, tautomer or stereoisomer thereof, or a pharmaceutical composition as defined in claim 46 , for the manufacture of a medicament.